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Male rats were dosed orally by gavage or were exposed dermally for six hours to 1 mg [phenyl-l4C(U)]-ODA. Urine and faeces were collected for a period of 48 hours following the oral gavage dose and for 24 hours following the dermal exposure. Organ and tissue distribution of radioactivity was determined for the dermal application group.

 

Approximately 35.3% and 28.1% of the radioactivity administered to the 0.5 and 200 mg/kg oral dose groups, respectively, was excreted in the urine by 48 hours after dosing; 10.7% of the radioactivity from the 0.5 mg/kg dose was excreted in the urine during the 12-hour post-dosing time interval as compared to 3.6% of the radioactivity from the 200 mg/kg dose. Approximately 28.7% of the radioactivity from the 0.5 mg/kg oral dose and 13.4% of the radioactivity from the 200 mg/kg oral dose was excreted in the faeces by 48 hours. Of the 28.7% excreted by the 0.5 mg/kg dose group, over 19% of the dose was excreted by 24 hours post dose as compared to only about 6% at the 200 mg/kg dose level.

 

Approximately 7.33% of the dermally applied 1 mg [phenyl-14C(U)]-ODA was absorbed into the systemic circulation during the six-hour application. Urinary excretion represented 3% of the absorbed dose with 2.46% being excreted in the 12- to 24-hour post-application urine sample. Approximately 0.09% of the applied dose was excreted in the faeces by 24 hours which represents approximately 0.9 pig of the total 1000 pig (1 mg) applied to the skin. Approximately 1.35% (0.98 u.g) of the absorbed dose (72.6 pig) was excreted in the faeces by the 24-hour sacrifice. Over 94%, of the absorbed dose remained in the tissues and carcass at the 24-hour sacrifice; of this, approximately 87% remained in the applied skin. Urine collected from the dermal penetration test group contained insufficient radioactivity for meaningful HPLC/radioactivity flow analysis.

 

Two urinary metabolites found in the 200 mg/kg oral dose group 12-hour urine, definitively identified and confirmed by LC-MS, and which co-eluted against authentic standards were monoacetylated ODA (N-ODA) and diacetylated ODA (N,N'-ODA). The remaining fractions were found to be co-elution mixtures of N-acetyl-ODA, N-acetyl hydroxylated-ODA, N-acetyl dihydroxylated-ODA, N,N'-diacetyl-ODA, and N,N'-diacetyl hyroxylated-ODA. Both N-ODA and N,N'-ODA change little in total abundance after glucoronidase/sulfatase enzyme hydrolysis of urine from the 200 mg/kg group.

 

The dermal application study show ODA is largely retained at the site of application. This suggests a potential for continued release of ODA or ODA-metabolites from the skin reservoir into the systemic circulation. The oral application study demonstrates the excretion of test substance via metabolisation, although absorption is not specified.

 

On the basis of this study alone, it is not possible to predict the overall potential for bioaccumulation.