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EC number: 939-350-2 | CAS number: -
No test substance-related mortality or morbidity were observed during the study. The only death observed (Male D28768, group 9, single oral dose at 50 mg/kg bw), was an isolated incident and not seen at the higher dose-level of 200 mg/kg bw, was considered to be due to complications following the bile duct cannulation. In terms of clinical signs, ptyalism was seen in 1/9 males and 1/9 females of group 5 from Day 6 (repeat oral dose of 50 mg/kg bw) and soft faeces were noted in 4/5 males of group 8 from Day 6 (also, repeat oral dose of 50 mg/kg bw). As the ptyalism was of low incidence and is often seen in rats treated orally, this was not considered to be test substance-related. In contrast, as of high incidence, the soft faeces were considered to be due to the repeated test substance treatment. No dermal irritation occurred.
Recovery: Total recovery for oral groups were sufficient with around 100% except for males of repeated dose group resulting to 95.3% recovery. For dermal groups, total recovery was slightly low (87.2% males and 91.0% females). However, it should be remarked that probably the total radioactivity in the carcass samples with an avarage of about 5% was too low, as for all 4 animals for which no separate internal organs were measured, total carcass levels were about 10%, compared to 1 to 3% for the 6 animals for wich radioactivity in individual organs were measured. -Oral application: Following single and/or repeated oral gavage at 50 and 200 mg/kg bw/day, 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. The vast majority of the oral dose was excreted rapidly in the faeces. At the high oral dose-level only, quantifiable levels of radioactivity were found in some central organs at 8 h post-dosing; otherwise, the vast majority of the dose was confined to the intestine and levels decreased over time. Only 0.62 to 8.15% of the oral dose was eliminated in the bile in a 24 h period.
-Dermal application: Following single dermal application at 1.5 and 15 mg/kg bw, 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 (the collar was worn during the 6 h exposure period only), 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 intestines, 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 intestines 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 intestine 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.
A guideline toxicokinetic study was conducted with C12-16 ADBAC. 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 hour 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 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.
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