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Description of key information

Toxicokinetics data from studies conducted under in vitro and in vivo conditions suggests that the read-across substance C12-16 ADBAC 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 as a worst-case approach even though with the most relevant and valid studies, a 1% dermal absorption would be a high estimate. An absorption of 100% was considered for the inhalation route.
The available data on dermal absorption does not allow the quantification of the dose which was absorbed after dermal application. However, based on the radioactivity recovered at the skin application site after removal of the stratum corneum layers (6.5-8.7% of the dose) and the ionic nature of the test item, it can be anticipated that the dermal absorption is not different from the oral one (10%). The primary effect involves disruption of the cytoplasmic membrane causing cell damage or lyses of the cell content. Due to adherence to negatively charged surfaces of the apolar alkyl chain, ADBAC substances will not easily pass biological membranes. Dermal uptake is therefore very limited at low, non-irritating concentrations.

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

Metabolism or transformation reactions of C12-14 ADBAC and the read-across substance C12-16 ADBAC in humans and animals were predicted by the metaprint2D tool. C12-16 ADBAC was also tested in experimental studies. The results obtained were in concordance.

The most frequently reported site for metabolism was the terminal two carbon position of the longer alkyl chain. There is also a reactive site at the para-position of the benzene ring. The reactions at these sites include hydroxylation, methoxylation and glutathionation. This is the well-known metabolism of aromatic systems and metabolites from these reactions do not alter the overall toxicity profile of the substance.

A guideline toxicokinetic study was conducted using radiolabelled C12-16 ADBAC. Rats were treated with single and repeated oral doses (50 or 200 mg/kg bw) as well as a single dermal dose of 1.5 or 15 mg/kg bw. Following single and/or repeated oral doses, 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 around 8% (urine and bile fractions). This was eliminated rapidly, essentially within a 48 to 72 hour period. The majority of the oral dose was excreted in the faeces. At the high oral dose level only, quantifiable levels of radioactivity (2,386 to 23,442 ηg equivalent/g) were found in some central organs at 8 hour 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 hour period, of which about 30% during the first 3 hours. Following a 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 hour period, suggesting that the dermal dose was highly absorbed via the skin. However, this apparent high absorption via the skin 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 the intestine and 4% excreted via urine. If similar routes of excretion are expected for dermally 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 dermally applied dose was taken up orally after all. According to the same oral kinetics, this leads to the 2% excretion in urine as indeed was observed. At 24 hours 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 hours, 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 thestratum corneumof 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 decreased over time (Appelqvist T, 2006).

In another study conducted according to EPA OPP 85-1, Sprague-Dawley rats (10 animals per sex per group) were treated with radiolabelled C12-16 ADBAC. The study was conducted in four experiments:

Experiment 1: single low dose (10 mg/kg);

Experiment 2: single high dose (50 mg/kg);

Experiment 3: 14-day 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 days.

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 amounts, 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 was 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 absorbed and that absorption is higher than the % found in the urine after oral administration. Less than 50% of the orally administered test substance was metabolised to side-chain oxidation products. In view of the limited absorption, the four 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).

In a guideline compliantin vitrostudy was conducted to determine the dermal absorption of C12-16 ADBAC. 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/hour. 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 10-3cm/hour was excluded from subsequent absorption measurements. Two test preparations containing [14C] - radiolabelled test substance (i.e., 0.03% and 0.3%), were applied at an application rate of 10 mg/cm2. Absorption was assessed by collecting receptor fluid in hourly intervals from 0-6 hours post dose and then in 2-hourly intervals from 6-24 hours post dose. At 24 hours 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 of14C- radiolabelled test substance in low (0.03%, w/w) and high (0.3%, w/w) concentration test preparations to human skin in vitro, the mean absorbed dose and mean dermal deliveries were 0.05% (<0.01 ηg equiv. /cm2) and 2.22% (0.07 ηg equivalent/cm2) of the applied dose for the low concentration test preparation, respectively, and 0.03% (0.01 ηg equivalent /cm2) and 2.16% (0.67 ηg equivalent/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 for the low and high concentration test preparations, respectively. The maximum fluxes for the low and high doses were 0.12 ηg equivalent /cm2/hour and 0.74 ηg equivalent /cm2/hour, respectively, at 2 hours (Roper C and Toner F, 2006).