Alfalfa metabolism of propham

Root-treated alfalfa absorbs, translocates, and metabolizes [phenyl-¹⁴C]isopropyl carbanilate ([¹⁴C]propham). After 7 days of root treatment, the distribution of radiolabel was 73% for shoots and 27% for roots. Shoots and roots were extracted and separated into the polar, nonpolar, and solid residual components using a mixture of chloroform, methanol and water. The insoluble residues accounted for approximately 40% of the ¹⁴C found in shoots and roots. The nonpolar fraction (6.1% of the radiolabel in shoots and roots) was not characterized, but was shown to be some component other than parent propham. Propham was not found in either shoots or roots. The polar metabolites were partly purified on Amberlite XAD-2. Cellulase-liberated aglycones were derivatized and separated by high-performance liquid and gas-liquid chromatography. The infrared, nuclear magnetic resonance, and mass spectral data showed that the polar metabolites of alfalfa shoots and roots were glycoside conjugates of isopropyl 2-hydroxycarbanilate (2-hydroxypropham) and isopropyl 4-hydroxycarbanilate (4-hydroxypropham). Conjugated 4-hydroxypropham accounted for 45.9% of the ¹⁴C in the shoots and 3.4% of the ¹⁴C in the roots. Conjugated 2-hydroxypropham accounted for 3.4% of the ¹⁴C in the shoots and 1.4% of the ¹⁴C in the roots.     

Mercapturic acid formation in the metabolism of propachlor,CDAA, and fluorodifen in the rat

When [¹⁴C]F₃-fluorodifen (2,4′-dinitro-4-trifluoromethyl diphenylether), carbonyl-[¹⁴C]CDAA (N,N-diallyl-2-chloroacetamide), and carbonyl-¹⁴C-propachlor (2-chloro-N-isopropylacetanilide) were fed to rats, 57 to 86% of the ¹⁴C was excreted via the urine within 48 hr. Although very little radioactivity was excreted in the feces of CDAA-treated rats, 15–22% of the ¹⁴C was excreted in the feces of propachlor- of fluorodifentreated rats and an average of 8% of the ¹⁴C remained in these rats 48 hr after treatment. Oxidation of the ¹⁴C label to [¹⁴C]O₂ was not a major process in the metabolism of these herbicides. The only major radioactive metabolite present in the 24-h urine of fluorodifen-treated rats, 2-nitro-4-trifluoromethylphenyl mercapturic acid, accounted for 41% of the administered dose of ¹⁴C. In the metabolism of CDAA, the corresponding mercapturic acid accounted for 76% of the dose; it was the only major metabolite present in the 24-h urine. In contrast, three major metabolites were detected in the 24-h urine of propachlortreated rats, and the mercapturic acid accounted for only 20% of the dose. The mercapturic acid of each herbicide was identified by mass spectrometry.     

The metabolism of the nonionic surfactant 14C-labeled α[p-1,1,3,3-tetramethylbutyl)phenyl]-ω-hydroxyhexa(oxyethylene) in the goat

A goat given a single dose of ¹⁴C-labeled α-[p-(1,1,3,3-tetramethylbutyl)phenyl]-ω-hydroxyhexa(oxyethylene) ([¹⁴C]TOP-6EOH) eliminated 18% of the ¹⁴C in the urine and 77% in the feces within 96 hr after dosing. Another goat (surgically modified for total bile collection) given a single dose of [¹⁴C]TOP-6EOH eliminated 81% of the ¹⁴C in the bile, 17% in the urine, and only 6% in the feces. When ¹⁴C-bile from the animal in the second study was perfused into the small intestine of a third goat, 72% of the ¹⁴C was eliminated in the feces, 20% in the bile, and 6% in the urine within 96 hr. Eighteen different types of metabolites accounting for most of the ¹⁴C in the bile and urine were isolated, derivatized, and then characterized by mass spectral analysis. The [¹⁴C]TOP-6EOH was metabolized by: (i) oxidation of the alkyl group to give alcohols and acids, (ii) oxidation of the terminal ethylene oxide moiety to an acid, (iii) cleavage of the polyoxyethylene side chain, (iv) combinations of i–iii, and (v) conjugation of the products of i–iv.     

Herbicide perfluidone (1,1,1-trifluoro-N-[2-methyl-4-(phenylsulfonyl)phenyl]methanesulfonamide): Its metabolism in rats and chickens

Rats and chickens were each given a single oral dose (10 or 100 mg/kg body wt) of 1,1,1-trifluoro-N-[2-methyl-4-(phenylsulfonyl)phenyl-¹⁴C(U)]methanesulfonamide ([¹⁴C]perfluidone). Depending on the size of the dose, from 8.4 to 36.2% of the [¹⁴C] was eliminated in the urine and from 36.4 to 85.4% was eliminated in the feces within 48 hr after dosing. Less than 1% of the [¹⁴C] given to laying hens as [¹⁴C]perfluidone was present in the eggs produced during the first 96 hr after dosing. The percentage of the administered [¹⁴C] that remained in these animals (body with G.I. tract and contents removed) varied from 0.34 (96 hr after dosing) to 1.68% (48 hr after dosing). ¹⁴C-labeled compunds in the urine and feces from the rats and chickens were purified by solvent extraction, column chromatography, and gas-liquid chromatography, and then identified by infrared and mass spectrometry. The parent compound was the major ¹⁴C-labeled component in the urine and feces of both animals. 1,1,1-Trifluoro-N-[2-methyl-4-(3-hydroxyphenylsulfonyl)phenyl]methanesulfonamide was present in the feces of both animals. The proposed structures of other metabolites were 1,1,1-trifluoro-N-hydroxy-N-[2-methyl-4-(phenylsulfonyl)phenyl]methanesulfonamide (rat urine) and 1,1,1-trifluoro-N-{2-methyl-4-[(methylsulfonyl)-phenylsulfonyl]phenyl}methanesulfonamide (chicken urine).     

Metabolism of methfuroxam (2,4,5-trimethyl-N-phenyl-3-furancarboxamide) in the rat and isolated rat hepatocytes

Isolated rat hepatocytes were incubated for 4 hr with [phenyl-U-¹⁴C]2,4,5-trimethyl-N-phenyl-3-furancarboxamide ([¹⁴C]methfuroxam). ¹⁴C-Labeled metabolites were isolated by solvent extraction, column chromatography, and high-pressure liquid chromatography, and were then characterized by analysis of infrared and mass spectra. Metabolism of [¹⁴C]methfuroxam by isolated hepatocytes included: (1) hydroxylation of the 2-, 4-, and 5-methyl groups on the furan ring; (2) hydroxylation at the para position of the benzene ring; (3) combinations of 1 and 2; (4) the addition of a sulfur-containing adjunct to the methylfuran moiety; and (5) conjugation of 1–4. Rats given a single intragastric dose of [¹⁴C]methfuroxam excreted 56% of the ¹⁴C in the urine and 42% in the feces within 54 hr. Metabolism of [¹⁴C]methfuroxam by the intact rats included: (1) hydroxylation of the methylfuran moiety; (2) hydroxylation of the benzene ring; (3) the addition of S-methyl, methyl sulfoxide, and other sulfur-containing groups to methfuroxam; (4) combinations of 1–3; and (5) conjugation of 1–4.     

Fate of captan and folpet in rats and their effects on isolated liver nuclei

Excretion and distribution of single and multiple intraperitoneal doses of [³⁵S]captan and [¹⁴C]folpet were similar in normal and 70% hepatectomized male rats. After receiving the single dose of captan, the rats eliminate approximately 76% of the radioactivity in the urine after 72 hr. The elimination in the feces for the same time period was 13%. Normal rats administered single or multiple doses of [¹⁴C]folpet excreted nearly 100% of the total dose in the urine within the first 24 hr. Nuclei isolated from the liver of normal and 70% hepatectomized rats receiving multiple doses of [³⁵S]captan contained 0.008–0.009 μg ³⁵S/g of tissue. Appreciable amounts of the radioactivity from [³⁵S]captan were bound by isolated nuclei from the livers of normal and partially hepatectomized rats. After a 1-hr treatment with [³⁶S]captan, the nuclei were fractionated into nuclear sap protein, deoxyribonucleoprotein (including histones), acidic ribonucleoprotein, and “residual” protein fractions. These proteins in normal nuclei bound 10, 14, 39, and 16% of the total label, respectively, with essentially the same results obtained with nuclei from regenerating rat liver. When compared by polyacrylamide gel electrophoresis, acidic nuclear proteins from treated and nontreated normal nuclei were characterized by band diffusion and the presence or absence of Amido Schwartz-staining bands. None of the abovementioned effects on histones from treated nuclei were observed. Captan treatment of isolated nuclei also altered the extraction characteristics of the nuclear protein fractions, presumably because of extensive aggregation of thiol-containing nuclear proteins.     

Biliary secretion of 14C and identification of 5,6-dihydro-5,6-dihydroxycarbaryl glucuronide as a biliary metabolite of [14C]carbaryl in the rat

The biliary secretion of ¹⁴C was observed in conscious, bile-fistulated rats given single oral doses of [¹⁴C]carbaryl (1.5, 30, and 300 mg/kg). Over 94% of the ¹⁴C was absorbed after 12 hr. From 15 to 46% of the ¹⁴C was secreted in bile, 10–40% in urine, and less than 1% in feces 12 hr after dosing. Three metabolites were isolated from bile and identified by mass and/or NMR spectrometric methods. These metabolites were: 5,6-dihydro-5,6-dihydroxycarbaryl glucuronide (12–18% of the biliary ¹⁴C), a conjugate(s) of carbaryl (12% of the biliary ¹⁴C), and conjugated isomers of hydroxy-carbaryl (2% of the biliary ¹⁴C). The majority of the biliary ¹⁴C remains to be identified.     

Metabolism of isopropyl carbanilate (propham) in alfalfa grown in nutrient solution

Alfalfa plants, Moapa variety, were grown in nutrient solution containing isopropylring-[¹⁴C] carbanilate (43.8 μCi/liter propham). After 8 days, 41.2% of the radioactivity initially added to the nutrient culture was recovered; 10.9% of this was from shoots, 3.4% from roots and 26.9% from nutrient medium. Nonextracted residues accounted for 23% of the radioactivity in shoots and 62% of that in roots. The parent herbicide constituted 53 and 38% of the radioactivity extracted from shoots and roots, respectively. The balance of extracted ¹⁴C was polar metabolites which were purified and subjected to enzymatic and acid hydrolysis. Four aglycones were isolated, three of which were purified by thin-layer chromatography and characterized by mass spectrometry. The principal aglycones were: isopropyl-2-hydroxycarbanilate, isopropyl-4-hydroxycarbanilate, and 1-hydroxy-2-propylcarbanilate. The fourth aglycone was not identified.     

The metabolism of the herbicide flamprop-methyl in rats and some comparative data for dogs,mice and rabbits

[¹⁴C]Flamprop-methyl administered orally to rats (3-4 mg kg^?1 body weight) was excreted mostly via the faeces (78.7 and 61.6% in males and females, respectively). Elimination was rapid and 90% of the dose of ¹⁴C was excreted in faeces and urine 0-48 h after dosing. The distribution of ¹⁴C between faeces and urine was different in males and females. No expired [¹⁴C]carbon dioxide was detected and less than 2% of the dose remained in the animals 4 days after dosing. The predominant metabolic pathway was hydrolysis of the ester bond to afford the carboxylic acid which was excreted unchanged and as its glucuronide conjugate. Aromatic hydroxylation occurred at the para- and meta-positions of the N-benzoyl ring. N-(3)-Chloro- 4-fluorophenyl-N-(3,4-dihydroxybenzoyl)-DL -alaninate was also formed. This hydroxylated form of flamprop-methyl was partially O-methylated at the 3-hydroxy group. Flamprop-methyl was also metabolised and eliminated rapidly by dogs, mice and rabbits. The last of these three species afforded very little aromatic hydroxylation and also differed from the others in that the metabolites were eliminated mostly in the urine. Aromatic hydroxylation lay in the order: male rat = female rat > dog= mouse>rabbit (female).     

Absorption and fate of imazapyr in leafy spurge (Euphorbia esula)

Imazapyr absorption, translocation, root release and metabolism were examined in leafy spurge (Euphorbia esula L.). Leafy spurge plants were propagated from root cuttings and [¹⁴C]imazapyr was applied to growth-chambergrown plants in a water + 28% urea ammonium nitrate + nonionic surfactant solution (98.75 + 1 + 0.25 by volume). Plants were harvested two and eight days after herbicide treatment (DAT) and divided into: treated leaf, stem and leaves above treated leaf, stem and leaves below the treated leaf, crown, root, dormant and elongated adventitious shoot buds. Imazapyr absorption increased from 62.5% 2 DAT to 80.0% 8 DAT. Herbicide translocation out of the treated leaf and accumulation in roots and adventitious shoot buds was apparent 2 DAT. By the end of the eight-day translocation period only 14% of applied ¹⁴C remained in the treated leaf, while 17% had translocated into the root system. Elongated and dormant adventitious shoot buds accumulated 3.2- and 1.8-fold more ¹⁴C, respectively, 8 DAT than did root tissue based on Bq g^?1 dry weight. Root release of ¹⁴C was evident 2 DAT, and by 8 DAT 19.4% of the ¹⁴C reaching the root system was released into the rooting medium. There was no metabolism of imazapyr in crown, root or adventitious shoot buds 2 DAT; however, imazapyr metabolism was evident in the treated leaf 2 and 8 DAT. Imazapyr phytotoxicity to leafy spurge appears to result from high imazapyr absorption, translocation to underground meristematic areas (roots and adventitious shoot buds), and a slow rate of metabolism.     

Alkylation of guanine in mice in vivo by organophosphorus insecticides. I. Trichlorphone and butonate

Following intraperitoneal administration to male mice of trichlorphone, 4 mg/animal = 160 mg/kg and butonate, 5 and 10 mg/animal = 200 and 400 mg/kg, labeled by ¹⁴C in the OCH₃-groups, nucleic acids taken from different organs and urine were analyzed for [7-¹⁴C]methylguanine. The limit of detection was 2 × 10^?8, calculated as ¹⁴C relative to the total dose. The maximum of ¹⁴C in 7-methylguanine was 2 × 10^?7 in lung, kidney, and testicles and 3 × 10^?6 in liver. The excretion rate of 7-MeG from nucleic acids is very rapid, a halflife of 2.0 hr was measured in liver from butonate and of < 24 hr was calculated in the whole body from trichlorphone, contrary to the excretion rate of 3.0–3.5 days following administration of strongly genotoxic agents. The relative amounts of [7-¹⁴C]methylguanine excreted in the urine were determined and compared with data for dichlorvos, dimethyl sulfate, and methyl methanesulfonate from the literature. Following intraperiotoneal administration, the methylating capability towards N-7 of guanine in nucleic acids is given by the ratio of about 100:10:25 for dichlorvos, butonate, and trichlorphone, respectively.     

Conversion of the aldrin/dieldrin metabolite dihydrochlordene dicarboxylic acid-14C in rats

Upon intravenous application of dihydrochlordene dicarboxylic acid-¹⁴C to rats, the radioactivity is quickly excreted, and 44% of the excreted radioactivity consists of metabolites. Nine metabolites have been isolated from feces and urine extracts. Three metabolites could be identified by means of authentic samples by thin layer chromatography, gas chromatography, and mass spectrometry: two isomers of dechlorodihydrochlordene-dicarboxylic acid (metabolites I and II, total 22.5%) and dihydrochlordene-dicarboxylic acid-dimethyl-ester (metabolite III, 11.3%).     

Physiological basis for antagonism of clethodim by imazapic on goosegrass (Eleusine indica (L.) Gaertn.)

Greenhouse and laboratory experiments were conducted to determine the effect of imazapic on the herbicidal activity of clethodim on goosegrass. Imazapic did not affect absorption of [¹⁴C]clethodim by goosegrass. Averaged across the two treatments of clethodim alone and clethodim plus imazapic, absorption was 36 and 89% of applied [¹⁴C]clethodim at 0.5 and 96 h, respectively. The majority of [¹⁴C]clethodim (79% of applied) was absorbed by 24 h. Translocation of ¹⁴C was not affected by imazapic, and 3.6% of applied ¹⁴C had translocated into the portion of the shoot below the treated leaf at 96 h after treatment. Metabolism of clethodim was not affected by the presence of imazapic. Three major metabolites of clethodim were detected in treated tissue at all harvest intervals. The majority (58%) of [¹⁴C]clethodim was converted to a relative polar metabolite form 96 h after treatment, whether clethodim was applied alone or in the presence of imazapic. One day after treatment, the photosynthetic rate in plants treated with imazapic decreased below the rate in the non-treated check, and was less for 8 days, the duration of the study. These data suggest that the antagonism of clethodim by imazapic may be caused by imazapic reducing the photosynthetic rate of goosegrass and therefore the sensitivity of ACCase to clethodim.     

A study of ethylene and CO2 evolution from ethephon in tobacco

Buffers and leaf discs of mature tobacco (Nicotiana tabacum L.) were utilized to study [¹⁴C]-ethylene and ¹⁴CO₂ evolution from radiolabeled ethephon, (2-chloroethyl)phosphonic acid. Metabolic fate of [¹⁴C]ethephon in leaf discs was investigated by use of thin-layer chromatography, high-voltage paper electrophoresis, autoradiography, and liquid scintillation spectroscopy. The evolution of labeled ethylene generally increased with increasing buffer pH, buffer volume, and dosage of [¹⁴C]ethephon. [¹⁴C]Ethylene was evolved, increasingly with time, from [¹⁴C]ethephon either added to the buffer or applied to leaf discs. The rate of [¹⁴C]ethylene evolution was maximum during the first day and leveled off on the fourth day. More than 50% of the total [¹⁴C]ethylene evolution over a 96-hr period was recovered during the first 24 hr after [¹⁴C]ethephon application. No ¹⁴CO₂ was evolved when [¹⁴C]ethephon was degraded in the presence of buffer or leaf discs. Only ethephon itself, and no detectable metabolite thereof, was discovered in the methanolic extract of the leaf disc tissue. An insignificant amount of ¹⁴C activity (approximately 2% of the extracted ¹⁴C) was detected in the residue. By means of gas chromatography, it was confirmed that in buffers and tobacco leaf tissue ethephon breaks down to release ethylene but not CO₂.     

Alachlor influence on sorghum growth and gibberellin precursor synthesis

Growth (14 days) of sorghum (Sorghum bicolor L. cv G522 DR) from seed planted in sand into which alachlor [2-chloro-2′,6′-diethyl-N-(methoxymethyl)acetanilide] was uniformly incorporated (0, 0.07, 0.14, 0.28, 0.56, 1.12, 2.24, or 4.48 kg/ha) was reduced by 0.14 kg/ha and severely inhibited (88%) by 0.56 kg/ha while cellular water cotent was not greatly influenced by 0.56 kg/ha. When added into the nutrient solution bathing the roots of 96-hr sorghum seedlings, alachlor (0, 0.0156, 0.0312, 0.0625, 0.125, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, or 128 ppmw) was not lethal to 14-day-old sorghum at rates up to 32 ppmw (92% survival); however, shoot and root lengths were reduced 43 and 58%, respectively. Alachlor inhibition of sorghum growth appears to be closely associated with inhibition of cell enlargement; the coleoptile is the most susceptible stage of sorghum growth to alachlor. This situation closely resembles growth where gibberellic acid (GA) synthesis is inhibited. [2-¹⁴C]Mevalonic acid ([2-¹⁴C]MVA) incorporation into terpenoid GA precursors was evaluated using a cell-free enzyme system from etiolated sorghum coleoptiles. Alachlor did not inhibit total ¹⁴C incorporation but incorporation of ¹⁴C into kaurenol and sterols was decreased ca 80 and 75%, respectively, by 10^?6M alachlor. Analyses for [¹⁴C]geranylgeraniol (GG), [¹⁴C]farnesol, and [¹⁴C]geraniol contents showed accumulation of [¹⁴C]farnesol and [¹⁴C]GG, and decreased [¹⁴C]geraniol. When seeds to which CGA-43089 [α-(cyanomethoximino)-benzacetonitrile] was applied 8 weeks prior to planting were substituted for untreated seeds, incorporation of [2-¹⁴C]MVA into [¹⁴C]kaurenol was increased by alachlor while [¹⁴C]GG and [¹⁴C]farnesol accumulated and [¹⁴C]geraniol was absent at 10^?6M alachlor. Additionally, sterol content increased in “safened” systems but was still decreased by alachlor. These data demonstrate multiple sites of alachlor activity in the GA and terpenoid biosynthetic pathway.     

Metabolic studies of 14C-labeled propham and chlorpropham in the female rat

The tissue distribution and excretion of ¹⁴C-labeled propham and chlorpropham were investigated in the adult female rat after a single oral dosage. The average 3-day urinary excretions of radioactivity were 55.9%, 82.6%, 79.5%, and 85.4% of an oral dose of chain [¹⁴C] chlorpropham, ring [¹⁴C] chlorpropham, chain [¹⁴C] propham, and ring [¹⁴C] propham, respectively. With chain [¹⁴C] chlorpropham 35.4 ± 7.5% of the administered radioactivity appeared in the respired air, whereas only 5.0 ± 0.8% was found in CO₂ from chain [¹⁴C] propham. There was no significant difference in the rate of excretion or the route of elimination among rats receiving different oral dosages, ranging from less than 4 mg/kg to 200 mg/kg. The radioactivity was distributed in all tissues with highest concentration found in the kidney. The average biological half-life of ¹⁴C from chlorpropham and propham in most organs was short, ranging between 3 and 8 hr; however, in brain, fat, and muscle, the half-life was about twice the value for other organs.Both compounds were metabolized by hydrolytic and oxidative mechanisms and the resulting metabolites were excreted either as free forms or as conjugates.Subcellular distribution of ¹⁴C in the rat liver and kidney after an oral administration of chlorpropham and propham was investigated. The percentage distribution of ¹⁴C in the particulate and soluble fractions was dependent on the elapsed time after dosing.     

Metabolism in rats of 3-phenoxybenzyl alcohol and 3-phenoxybenzoic acid glucoside conjugates formed in plants

Upon single oral administration to rats, the mono-, di- and tri-glucose conjugates of [¹⁴C]-3-phenoxybenzyl alcohol ( I ) or the mono-glucose conjugate of [¹⁴C]-3-phenoxybenzoic acid ( II ) were rapidly hydrolysed and extensively eliminated in the urine mostly as the sulphate conjugate of 3-(4-hydroxyphenoxy)benzoic acid ( X ). The faecal elimination was a minor route, whereas the biliary excretion was about 42% of the dose and the glucuronide conjugates of I , II and X were common major metabolites. The biliary glucuronides were cleaved in the small intestine to the respective aglycones, which were reabsorbed, metabolised further, and excreted in the urine as the sulphate conjugate of X . Although small amounts of the mono-, di-and tri-glucosides were found in the 0.5-h blood and liver samples following oral administration of the tri-glucoside of I , they were not detected in the urine, bile or faeces. Similarly the sulphate conjugate was one of the major urinary metabolites of germ-free rats, dosed with the ¹⁴C-glucosides via the oral or the intraperitoneal route, although they were excreted unchanged in certain amounts in the urine and faeces. The glucose conjugates were cleaved in vitro by gut microflora and in various rat tissues, including blood, liver, small intestine and small intestinal mucosa. The tissue enzymes showed a different substrate specificity in hydrolysis of the glucosides. However, they were not cleaved in gastric juice, bile, pancreatic juice or urine.     

The metabolism of benodanil in the rat

The metabolism of benodanil (2-iodobenzanilide) was studied in rats following an oral dose of 150 mg benodanil kg^?1 body weight. The major 24-h urinary metabolite was found to be the 4′-hydroxy derivative, both free (≈ 5%) and as the glucuronide (≈ 4%) and sulphate (≈ 4%) conjugates. Over a 6-day period, about 16% of the administered dose was excreted in the urine and about 80% in the faeces. After dosing with [¹⁴C]- benodanil, blood radioactivity levels were highest 30 min after dosing, with small broader peaks at 4 and 7 h, while biliary activity levels rose slowly to a maximum about 10–12 h after the dose, some 16% being excreted in 24 h as the glucuronide conjugate of the 4′-hydroxy derivative.     

The metabolic fate of tridemorph in rats

A single oral dose of [¹⁴C]tridemorph was partly, but rapidly absorbed by rats. Most of the radioactivity was excreted with a half-life of about 15 h. During 5 days, 42.6% was excreted in the urine, 46.7% in the faeces, 1.5% in the expired air and 3.4 % was still retained. 24 % was excreted in the 48 h bile. Sequential wholebody autoradiography indicated that much of the radioactivity was confined to the gastrointestinal tract, liver and kidneys. There was no unexpected uptake of radioactivity. Urinary metabolites were more polar than tridemorph and were also detected in the bile and faeces. The major metabolite in 24 h urine, accounting for 22.3% of the dose appeared to be a side-chain hydroxylated derivative. Cleavage of the morpholine ring was limited to about 1.5 % of the dose.     

Fate of endosulfan in rats and toxicological considerations of apolar metabolites

[¹⁴C]Endosulfan, α or β isomers separately, was administered to rats as a single oral dose and as a dietary supplement for 14 days. No appreciable differences were observed in the fate of the two isomers. Five days after the single dose, 75% of the dose had been voided in the feces and 13% in the urine. Of the total radiocarbon consumed in the diet after 14 days, 56% had been eliminated in the feces and 8% in the urine. Bile collection studies showed that up to 47% of a single oral dose was eliminated from the liver via this route; enterohepatic circulation was not apparent. Maximum [¹⁴C]endosulfan equivalents in body tissue occurred in the kidney and liver, 3 and 1 ppm, respectively, after 14 days of feeding 5 ppm of endosulfan. Apolar metabolites in the excreta and/or tissues were a minor portion of the total residues and consisted of the sulfate, diol, α-hydroxy ether, lactone, and ether derivatives of endosulfan. The sulfate was slightly more toxic to mice than endosulfan, while the other products were less toxic. Neither endosulfan nor its metabolites were active in the Salmonella mutagenicity test. Endosulfan in the diet of rats for 28 days at 50 ppm did not induce liver oxidase enzymes, alter liver or kidney weights, or influence the rate of weight gain of the animals.