Hiroyasu Kaneshima

Acute toxicity, percutaneous absorption and effects on hepatic mixed function oxidase activities of 2,4,4′-trichloro-2′-hydroxydiphenyl ether (Irgasan® DP300) and its chlorinated derivatives

Acute toxicity of 2,4,4′-trichloro-2′-hydroxydiphenyl ether (Irgasan® DP300) (I) and its three chlorinated derivatives, 2′,3,4,4′-tetrachloro-2-hydroxydiphenyl ether (II), 2′,4,4′,5-tetrachloro-2-hydroxydiphenyl ether (III) and 2′,3,4,4′,5-pentachloro-2-hydroxydiphenyl ether (IV), in mice were examined by intraperitoneal injection. The LD50 values of Irgasan DP300, II, III and IV were 1,090, 710, 650 and 430 mg/kg, respectively.The percutaneous absorptions of these tritiated compounds were also examined by the application on the backs of mice. The radioactivities in most tissues reached to the maximal levels at 12 h or 18 h after dosing, which corresponded to 11–76% of the maximal levels given by the oral administration (Kanetoshi et al. 1988a). These results show the high percutaneous absorbability of Irgasan DP300 and its chlorinated derivatives.The intraperitoneal administrations of III and IV to rats induced hepatic microsomal aminopyrine N-demethylase and aniline 4-hydroxylase activities similarly to phenobarbital. These chlorinated derivatives also increased cytochrome P-450 content, and the activities of aminopyrine N-demethylase and N-methylaniline N-demethylase in hepatic microsomes from mice. The extents of the increases were similar to those by phenobarbital and 3-methylcholanthrene.

Formation of polychlorinated dibenzo-p-dioxin from 2,4,4'-trichloro-2'-hydroxydiphenyl ether (irgasan® DP300) and its chlorinated derivatives by exposure to sunlight

Exposure to sunlight in the solid state of 2,4,4′-trichloro-2′-hydroxydiphenyl ether (Irgasan® DP300) (I) produced dichlorodibenzo-p-dioxin(s) (di-CDD) and a trace amount of trichlorodibenzo-p-dioxin (tri-CDD) together with three chlorinated derivatives of Irgasan DP300, 2′,3,4,4′-tetrachloro-2-hydroxydiphenyl ether (II), 2′,4,4′,5-tetrachloro-2-hydroxydiphenyl ether (III) and 2′,3,4,4′,5-pentachloro-2-hydroxydiphenyl ether (IV). These chlorinated derivatives gave various polychlorinated dibenzo-p-dioxins (PCDDs) upon exposure to sunlight; i.e., II gave 1,2,8-tri-CDD and a tetrachlorodibenzo-p-dioxin (tetra-CDD); III gave di-CDD(s), 2,3,7-tri-CDD and a tetra-CDD and IV gave three pentachlorodibenzo-p-dioxins (penta-CDDs) with two tri-CDDs and four tetra-CDDs. Upon exposure to sunlight of commercial textile products containing Irgasan DP300, 0.02–0.03% of the agent was converted into di-CDD(s). These results suggest that Irgasan DP300 is one of the precursors of various PCDDs in the environment.

Disposition and excretion of Irgasan DP300 and its chlorinated derivatives in mice.

The distributions of radioactivity were examined by whole body autoradiography and liquid scintillation spectrophotometry in male ddY mice following oral administration of tritium-labelled Irgasan® DP300 (2,4,4′-trichloro-2′-hydroxydiphenyl ether) (I) and its three chlorinated derivatives; 2′,3,4,4′-tetrachloro-2-hydroxydiphenyl ether (II), 2′,4,4′,5-tetrachloro-2-hydroxydiphenyl ether (III) and 2′,3,4,4′,5-pentachloro-2-hydroxydiphenyl ether (IV). The autoradiograms at 6 or 24 hr showed that the radioactivity distributed in the gall, liver, lung, heart, and kidneys. Among these tissues the radioactivity was most concentrated in the gall, suggesting the enterohepatic circulation of these compounds. A much higher level of radioactivity in each tissue was observed in mice receiving [3H]-III than the other compounds tested. Most of the radioactivity disappeared from each tissue in 24 hr due to [3H]-Irgasan DP300, [3H]-II or [3H]-IV, but in 96 hr it was due to [3H]-III.The cumulative radioactivity excreted in urine after administration of these compounds was in the order of [3H]-Irgasan DP300, [3H]-II, [3H]-IV and [3H]-III while that in feces was in the order of [3H]-IV, [3H]-III, [3H]-II and [3H]-Irgasan DP300,