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Description of key information

Short description of key information on bioaccumulation potential result: 
DCP is rapidly absorbed, metabolised and eliminated by both the oral and inhalation routes of exposure.

Key value for chemical safety assessment

Additional information

Information is available on the toxicokinetics and metabolism of [14C]-PDC in F344 rats following oral administration and inhalation exposure. These investigations were conducted in accordance with EPA test-rule requirements and were GLP compliant. In the oral studies, animals were given either single (1 or 100 mg/kg bw) or multiple (1 mg/kg bw/day on 8 consecutive days) gavage treatments with radiolabelled 14C-PDC in corn oil, while inhalation exposure involved a 6 hr head-only exposure (0, 5, 50 or 100 ppm). Elimination pathways and the time-course for excretion were evaluated by collection of excreta (urine, faeces) and exhaled air over 48 hr. Tissue distribution of radioactivity was determined after terminal sacrifice. Structural quantitation of major urinary metabolites was also carried out.

The results demonstrated rapid absorption, metabolism, and excretion irrespective of the route of exposure. Urine was the principle route of elimination (accounting for 40-65% of recovered radioactivity), followed by expired air (20-40% of recovered radioactivity). The major urinary metabolites were identified as three N-acetylcysteine conjugates of PDC, while 14C-CO2 predominated in exhaled air with smaller amounts (generally 1-10%) of unchanged parent substance. The tissues/carcass, feces, and cage wash contained less than 11%, 10%, and 4% of the recovered radioactivity, respectively. Liver contained the greatest amount of radioactivity (<0.4% of dose per g wet weight) with small amounts present in all other tissues sampled (generally <0.1% of dose per g wet wt), indicating that PDC was distributed to all tissues, including bone. Peak plasma radioactivity was generally attained 4 hr post-treatment, irrespective of route, but Area Under the Curve (AUC) values were less than dose-proportionate in the higher oral (100 mg/kg) and inhalation (50 or 100 ppm) groups, possibly indicating saturation of uptake, enhanced excretion, or a greater volume of distribution.

Discussion on bioaccumulation potential result:

Following single oral gavage administration (1 or 100mg/kg) to male and female F344 rats, DCP was rapidly and extensively eliminated via the urine and exhaled air. Over two-thirds of a single dose was found in the urine (46-52%) and exhaled air (23-36%), with most of this being collected during the first 24h post-dosing. Exhaled radioactivity was primarily in the form of CO2, although there was a significant shift towards exhaled volatile organics (predominantly parent compound) in high-dose animals. The pattern of elimination was similar in animals treated with eight daily doses of 1mg/kg, although urinary excretion was slightly lower and elimination of 14C-CO2 was slightly greater. The plasma profile showed a peak at 4h post-dosing, which was slightly less than dose-proportionate at the higher dose (plasma concentrations of 0.3-0.4 ug eq/g and 24-28 ug eq/g with corresponding AUC values of 4.2-5.4 ug/g and 351-368 ug/g respectively). Urinary analysis showed radioactivity associated with 4 peaks, the major one of which consisted of three N-acetylcysteine conjugates of DCP, N-acetyl-S-(2-hydroxypropyl)-L-cysteine, N-acetyl-S-(2-oxopropyl)-L-cysteine and N-acetyl-S-(1-carboxyethyl)-L-cysteine, although the radioactivity associated with the other peaks was not resolved. Inhalation exposure (5, 50, or 100ppm) showed a similar profile of metabolism and elimination as to that from the oral route.