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The metabolic fate of S-methyl-C14, ferf-butyl-C14, and N-methyl-C14 Temik [2-methyl-2-(methylthio)propionaldehyde 0-(methylcarbamoyl)oxime] was investigated in the rat. The over-all recovery of the S-methyl, ferf-butyl, and N-methyl label was, respectively, 95, 96 and 72% of the doses. Tissue residues (8 to 10% of the dose) were found only in the case of N-methyl labeled Temik. Seventy per cent of an oral dose of Temik was excreted as 2-methyl-2-(methylsulfinyl)propionaldehyde oxime and 2methyl-2-(methylsulfinyl)propionaldehyde 0-(methylcarbamoyl)oxime.The remaining metabolites appeared to be acids formed by further oxidation of the oxime. In conjunction with the metabolic studies, in vivo cholinesterase depression and recovery curves were obtained with plasma, red blood cells, and brain. At an oral dose of 0.33 mg. per kg., the cholinesterase activity of Temik-treated rats recovered from inhibition two hours prior to the rats treated with 2-methyl-2-(methylsulfinyl)propionaldehyde O-(methylcarbarnoyl)oxime.

1. [1,2]-14C-Ethylene glycol (EG) was given to female CD (Sprague-Dawley) rats and CD-1 mice in order to determine tissue distribution and metabolic fate after intravenous (iv), peroral (po), and percutaneous (pc) doses. Rats were given doses of 10 or 1000 mg/kg by each route, and additional pc doses of 400, 600 or 800 mg/kg. Mice were also given iv and po doses of 10 or 1000 mg/kg, and intermediate po doses of 100, 200 or 400 mg/kg. Mice were given po doses of 100 or 1000 mg/kg, and both species were given a 50% (w/w) aqueous po dose to simulate antifreeze exposure. 2. For both species, EG is very rapidly and almost completely adsorbed after po doses. Perorally administered EG doses produced similar dose-dependent relationships described in prior studies for the disposition and excretion of iv doses. 3. The tissue distribution of EG following either iv or po routes was essentially the same, with similar percentages recovered for each dose by both routes and for either species. 4. Cutaneously-applied EG was slowly and rather poorly adsorbed in both species, in comparison with po-dose administration, and urinalysis after undiluted po doses indicated that EG probably penetrates rat skin in the parent form. There was an absence in both species of dose-dependent changes in disposition and elimination following the pc application of EG. 5. 14C-labelled EG, glycolic acid and/or oxalic acid accounted for the majority of the detectable radioactivity in the urine samples from all dose routes in the rat, while glycoaldehyde and glyoxylic acid were not detected in any of the urine fractions evaluated. Similar increases in glycolate production with increasing dose were also observed in mouse urine samples from iv and po dosing. Also, glyoxylate and oxalate were absent from mouse urine. 6. Oxidative metabolic pathways appeared to be saturated at high po doses in both species, resulting in a shift from principally 14CO2 exhalation to urinary 14C excretion, while the onset of capacity-limited metabolic changes appears to occur at lower doses for mice than for rats. 7. In summary, rats and mice displayed several similarities in the manner in which low doses of EG by several routes are distributed, metabolized, and excreted, but the onset of capacity-limited changes in metabolism occurs at lower doses for mice than for rats. Such differences in the disposition of EG may provide important interpretive information to help explain differences observed in developmental toxicity and nephrotoxic responses between these two rodent species.

Further studies of the metabolism of carbaryl in the rat at 30 mg per kg body weight in a single oral dose have qualitatively reproduced the chromatographic profiles from urines of rats obtained by Knaak et al. (1965) on diethylaminoethyl cellulose columns after single oral and intraperitoneal dose studies. An attempt to verify the structure of a metabolite suspected of being 1-naphthyl methylimidocarbonate 0-glucuronide (Knaak et al., 1965) has failed to confirm the hypothesis. The principal aglycone isolated from the ether-extractable fraction of an enzyme hydrolysate of this metabolite has been identified as 5,6-dihydro-5,6-dihydroxycarbaryl. When losses and unhydrolyzed glucuronide are proportioned between this aglycone and others isolated, 10.5% of the dose is excreted as the 5,6-dihydro-5,6-dihydroxycarbaryl glucuronide calculated as carbaryl equivalents.arbaryl (1 -naphthyl methylcarbamate) metabolism was first investigated by Carpenter et al. (1961). They C reported that approximately 30 % of the dose could be determined as 1 -naphthol using a colorimetric procedure. Dorough and Casida (1964) using fortified liver microsomes found hydroxylated products of carbaryl. Knaak et al. (1965) using methyl, carbonyl, and naphthyl-labeled carbaryl and diethylaminoethyl cellulose chromatography analyzed the urine of rats and guinea pigs for the conjugated metabolites and found 80 to 90 of the urinary metabolites to be anionic. In addition to the glucuronide and sulfate conjugates of 1-naphthol and 4-hydroxycarbaryl (4-hydroxy-1 -naphthyl methylcarbamate), these authors found a metabolite of carbaryl suspected of being 1-naphthyl methylimidocarbonate 0-glucuronide. A chromatographically similar metabolite was found in the urines of the monkey, pig, and sheep (Knaak et al., 1968) and possibly the dog (Knaak and Sullivan, 1967). Because this compound was excreted by a number of species, a program was undertaken to examine the nature and quantitative aspects of the metabolite. METHODS Chemicals.Carbaryl-methyl-' 4C (0.93 mCi per mmol) and carbaryl-1-naphthyl-' 4C (0.97 mCi per mmol) were prepared by T. E. N. Steele, Tuxedo, N. Y., as described by Knaak et al. (1965). Carbaryl-carbonyl-' 4C with a specific activity of 1.5 mCi per mmol was purchased from Volk Radiochemical Co., Chicago, Ill. The samples were shown to be 99% carbaryl-' 4C when gas chromatographed as their N-acetyl derivatives on a 5 % SE-30 column (Sullivan et al., 1967).Nonlabeled carbaryl, 5,6-dihydro-5,6-dihydroxycarbaryl, 4-and 5-hydroxycarbaryl (4-and 5-hydroxy-1-naphthyl methylcarbamate), and 1-naphthol were supplied by Union Carbide, Chemicals and Plastics Operating Division, South Charleston, W. Va. Treatment and Handling of Animals. Naphthyl-' 4C, methyl-l4C, and carbonyl-14C carbaryl (0.8, 1.4, and 0.53 pCi per mg, respectively), dissolved in polyethyleneglycol 400, were administered individually by the peroral route to groups of 12, 150-g male rats at 30 mg per kg. First-day urines were collected and pooled separately according to label. ...

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