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To study the absorption, distribution, metabolism, and excretion of CS-1246, rats (four male and female rats per treatment group) were either dosed orally (5 or 200 mg/kg) or dermally (5 mg/kg) with14C-CS-1246 (Saghir et al., 2008). The orally administered CS-1246 biocide was rapidly absorbed (85 to 99%) without any apparent lag time. Absorption via skin was 25-27% of applied dose. Total recovery of radioactivity from the orally dosed rats was 91-109% of the administered dose. Recovery of the dermally applied dose was 66-70%. The lower recovery was considered to be due to volatilization of the test material and/or degradation of parent compound. 

 

The orally absorbed dose was rapidly excreted in urine (83-97%) without any gender difference. Most of the urinary elimination (61-75%) occurred within 12 hours (~43% within 6 hours) of dosing with additional 9-12% during 12-24 hours post-dosing. Total fecal elimination of the dermal dose was only 4% (15-16% of the absorbed dose Elimination of the dermally applied dose was slower with 17-20% of the applied dose being eliminated within 24 hours of dosing. 

Only ~1% of the orally administered14C-CS-1246 biocide remained in the tissues after 144 or 168 hours post-dosing. An average of 3% of the dermally dosed14C-CS-1246 remained in the tissues of the animals sacrificed 168 hours post-dosing, most of the remaining radioactivity, (i.e. 2.6 to 2.7%) was found in skin remote from the application site and only 0.8 to 1.7% was recovered from the application site skin. Such a low difference in the residual radioactivity between the dosed site skin and skin at other sites of the body was an indication that complete absorption had been achieved and any additional penetration of radioactivity from the application site was not likely to occur.

 

In the rats dosed orally with14C-CS-1246, elimination of the radioactivity from plasma was biphasic with most of the elimination occurring during the rapid (a) elimination phase (t½α= 0.1-0.5 hours), with a slower (b) elimination phase (t½b= 4-5 hours). There was some indication of enterohepatic circulation of the biliary eliminated radioactivity between 2-6 hours post-dosing in the low-dose rats, which became pronounced at the high dose. The AUC of radioactivity in plasma at the high dose was 270-281 µg h g-1, which was largely dose proportional; 44-49 fold higher than that observed at the low dose. Consistent with dose proportionally of Cmax, AUC and unsaturated kinetics between the low and high doses, clearance remained unchanged between the two doses.

 

The absorbed test material was completely metabolized, affording 2-amino-2-ethyl-1,3-propanediol (AEPD) as the only metabolite above 5% of the administered dose in all urine and fecal samples analyzed from all dose groups. Four minor metabolites were also observed above 0.5% of the administered dose, but not identified.

 

Overall Evaluation of Kinetic and Metabolism Data

In summary, orally administered CS-1246 biocide was rapidly and efficiently absorbed (85 to 99% of applied dose), completely metabolized and readily eliminated from the rat within 144-168 hours after dosing. The dermal dose of CS-1246 was less efficiently absorbed (25 to 27% of applied dose) but as with the orally applied dose the material was completely metabolized and readily eliminated from the body. These data show that accumulation of CS-1246 or any of the metabolites will not occur even with repeat exposures. 

References:

Saghir,, Clark, A. J., Beuthin, D.J., McClymont, E. L. and Staley, J. L. (2008)BIOBANÔCS-1246BIOCIDE: Pharmacokinetics and Metabolism in Crl: CD(SD) Rats. The Dow Chemical Company Report No: DR-0365-7827-010 GLP, Unpublished