Mode of action of meturine

The effect of meturine on the light processes of photosynthesis was studied.Meturine is a herbicide for weed control in potato and cotton crops. It is a N-phenyl—N-hydroxy—N′-methylurea.The experiments were carried out on isolated pea and spinach chloroplasts.When examining photosystem I, reduced DPIP was used as an electron donor, whereas methyl-viologen served as an electron acceptor. When examining photosystem II, DPIP represented the electron acceptor.The obtained experimental results have pointed to the absence of the effect of meturine upon the photoreaction I.Unlike N-phenyl—N′, N′-dimethylureas (CMU, DCMU) meturine has been a very weak inhibitor of photoreaction II.The authors explain the photoreaction II inhibition of chloroplasts from plants treated with herbicidal doses of meturine by conversion of N-phenyl—N-hydroxy—N′-methylurea into Hill reaction inhibitor(s). N-Phenyl—N′-methylurea can be one of such meturine metabolites.Meturine herbicidal action is accounted for by meturine transformation into Hill reaction inhibitor(s) in the plant tissues.     

Quantitative structure-activity studies of benzoylphenylurea larvicides: I. Effect of substituents at aniline moiety against Chilo suppressalis walker

The larvicidal activity of a series of N-2,6-difluoro- and N-2,6-dichlorobenzoyl-N′-(4-substituted phenyl)ureas against nondiapause larvae of the rice stem borer, Chilo suppressalis Walker, was measured by topical application and oral administration methods under conditions with and without piperonyl butoxide as an inhibitor of oxidative metabolism. The effects of substituents at the anilide moiety on the larvicidal activity were analyzed quantitatively using physicochemical substituent parameters and regression analysis. The results indicate that the oxidative metabolism in the larval body which is favored by electron-donating substituents is significant in determining the activity. The activity, when the metabolic factor is eliminated, is enhanced by electron-with-drawing and hydrophobic substituents and lowered by bulky groups. The inhibitory activity against new cuticle formation of the same series of compounds was also measured using cultured integument of the rice stem borer diapause larva. The comparison of the quantitative analyses between larvicidal and integument-level activities shows that inhibition of cuticular development is the most important factor governing larvicidal activity.     

Metabolism of a phosphoramidate by Pyricularia oryzae in relation to tolerance and synergism by a phosphorothiolate and isoprothiolane

Metabolism of dibutyl N-methyl-N-phenylphosphoramidate (BPA) by mycelial cells of Pyricularia oryzae was studied to elucidate the mechanism of synergism and negatively correlated cross-resistance in fungicidal action between phosphoramidates and phosphorothiolate derivatives. Rapid metabolism of BPA by a wild-type strain through hydroxylation and N-demethylation was observed. The metabolism was inhibited by diisopropyl S-benzyl phosphorothiolate (IBP; Kitazin P) and by isoprothiolane (diisopropyl 1,3-dithiolan-2-ylidenemalonate; Fuji-One). This inhibition of BPA metabolism is probably the mechanism of synergistic fungicidal action between the phosphoramidate and the thiol derivatives. The metabolism was, however, not inhibited by S-1358 (S-butyl S′-p-tert-butylbenzyl N-3-pyridyldithiocarbonimidate; Denmert) or triarimol [α-(2,4-dichlorophenyl)-α-phenyl-5-pyrimidinemethanol; EL-273], both of which are considered to be inhibitors of hydroxylation of a methyl radical in ergosterol biosynthesis. The metabolism of BPA by P. oryzae was much slower when mutants selected for IBP resistance and for isoprothiolane resistance were used. This phenomenon probably explains the differential sensitivity to phosphoramidate of wild-type strains and mutants resistant to the thiol derivatives.     

1-(2,6-disubstituted benzoyl)-3-phenylurea insecticides: Inhibitors of chitin synthesis

The mode of action has been investigated of the 1-(2,6-dichlorobenzoyl)-3-phenyl ureas, a new type of insecticide. A microautoradiographical study was made of the incorporation of glucose, tyrosine, and proline in endocuticle of fifth-instar larvae of Pieris brassicae L., both normal and treated with 1-(2,6-dichlorobenzoyl)-3-(3,4-dichlorophenyl)-urea (DU 19111). The results of this work clearly indicate that DU 19111 blocks the synthesis of cuticular chitin. The nature of this inhibition was investigated by comparison of the rates of incorporation of [¹⁴C]glucose into the ultimate chitin precursor, uridine diphosphate N-acetyl glucosamine (UDPAG), in both normal and DU 19111-treated Pieris larvae. It was found that these levels did not differ significantly.The finding that only in DU 19111-treated Pieris larvae were substantial amounts of labeled N-acetyl glucosamine present 1 hr after the injection of [¹⁴C]glucose is considered as a clue to the mechanism by which this insecticide inhibits chitin synthesis. Apparently the coupling of UDPAG to the chitin synthetase still proceeds, but the function of connecting N-acetyl glucosamine moieties to the chitin chain is disrupted.Tentative results with a structural analog of DU 19111 suggest that this compound induces accumulation of UDPAG, but not of N-acetyl glucosamine. This would imply that in the latter case the polycondensing enzyme is completely blocked.     

Induction of hyperactivity in larvae of the cattle tick Boophilus microplus by formamidines and related compounds

The effect of chlordimeform and 18 related compounds on the aggregation behavior of the negatively geotactic larvae of the cattle tick, Boophilus microplus was investigated. Aggregations were treated and hyperactivity in the forms of immediate dispersal, delayed dispersal, and prolonged leg waving evaluated. A marked structure-activity relationship with delayed dispersal resulted; most active were the N-monomethyl formamidines, N′-(2,4-dimethylphenyl)-N-methylformamidine and demethylchlordimeform. Other compounds, including chlordimeform, with structures compatible with metabolism to N-monomethyl formamidines were also active. Delayed dispersal caused by those possessing the N,N-dimethyl moiety was antagonized after inhibition of oxidative N-demethylation to N-monomethyl analogs by piperonyl butoxide. Since the N-monomethyl moiety had already been reported as important in the killing action of the formamidines in cattle tick larvae, the possibility of a relationship between delayed dispersal and acaricidal effectiveness was examined and percentage mortality at 24 hr found to correlate positively with the rate of onset of dispersal.Delayed dispersal was not characteristic of the responses to other acaricides such as lindane, allethrin, carbaryl, and coumaphos. In addition, the monoamine oxidase inhibitors, tranylcypromine, pargyline, and nialamide, did not induce delayed dispersal and showed no lethal effects.     

Chitin biosynthesis inhibition and fungicidal effect of thiosemicarbazones of 2-formyl- and 2-acetylpyridine,their hydrogenated derivatives and copper complexes thereof

Several thiosemicarbazones of 2-formyl- and 2-acetylpyridine dialkylated on N⁴ and non-alkylated on N² were found to be broad-spectrum protectant fungicides with activity particularly against oomycetes. The effect of some of the compounds on chitin biosynthesis was studied, but the low inhibitory activity observed combined with the fungicidal activity spectrum—particularly the high activity against oomycetes—excludes this as their main mode of action. Attempts at enhancing the systemic properties of the compounds by chemical modifications failed.     

In vitro activity of sorghum-selective fluorophenyl urea herbicides

The use of N-cyclopropyl-N′-(2-fluorophenyl) urea as a selective herbicide in grain sorghum has recently been disclosed (U.S.P. 4,344,916). Evaluation of analogs of this compound has included two assays on isolated pea chloroplasts—photosynthetic electron transport and competition for atrazine binding sites. Of all the analogs studied in at least one of these assays, the most active in vitro were the N-cyclopropyl-, N-n-butyl-, and N-n-pentyl-derivatives of 2,5-difluorophenyl urea. The two in vitro assays correlated well with each other, and binding activity demonstrated a strong correlation with whole-plant phytotoxicity following postemergence application. Several postulated sorghum metabolites of N-cyclopropyl-N′-(2-fluorophenyl) urea showed weak or no activity in vitro, as would be expected from the compoud's selectivity properties.     

Inhibition of chitin synthesis by two 1-(2,6-disubstituted benzoyl)-3-phenylurea insecticides. II

The knowledge of the biochemical mode of action of 1-(4-chlorophenyl)-3-(2,6-difluorobenzoyl)urea (diflubenzuron) is presented, explaining the insecticidal effect. Like its structural analog, 1-(2,6-dichlorobenzyl)-3-(3,4-dichlorophenyl)urea (Du 19111), it inhibits chitin synthesis in the cuticle of larvae. Virtually complete inhibition was demonstrable 15 min after the application of diflubenzuron. Neither diflubenzuron nor Du 19111 has any effect upon chitinase activity either in vivo or in vitro. The insecticidal effect upon the cuticle, therefore, must be explained as an inhibition of chitin synthesis and not as an activation of chitin degradation. In contrast to the action of Du 19111, no accumulation of N-acetylglucosamine occurs upon treatment of larvae with diflubenzuron. Similarities and differences in the mode of action of both compounds are discussed, together with other effects reported in the literature.     

Quantitative structure-activity relationships of herbicidal N′-substituted phenyl-N-methoxy-N-methylureas

Relationships between three types of herbicidal activity of N′-substituted phenyl-N-methoxy-N-methylureas and substitution at the benzene ring were analyzed by the Hansch-Fujita method. First, the Hill inhibitory activity was correlated with electronic (σ) as well as hydrophobic (π) substituent constants. The existence of an optimum value of hydrophobicity for substituents was suggested to reach the target site of action. Second, bliaching activity observed for the 3-substituted but not for 4-substituted compounds was correlated with π, σ, and steric substituent constant, E_s. Third, the postemergent herbicidal activity was shown to correlate linearly with the Hill inhibitory activity, pI₅₀, and hydrophobic parameter, π.     

Inhibition of Tribolium gut chitin synthetase

The chitin synthetase (CS) of Tribolium castaneum gut is inhibited 50% by 0.02 μM nikkomycin and 4 μM polyoxin D, two pyrimidine nucleoside fungicides, in in vitro assays with 10-min preincubation of enzyme and inhibitor prior to substrate addition. Tribolium CS is also sensitive to inhibition by the pyrimidine nucleotides uridine and cytidine di- and triphosphates. Captan, a known inhibitor of insect chitin synthesis, and the related fungicides captafol and dichlofluanid are highly potent inhibitors of Tribolium CS. Moderately active CS inhibitors are the acaricide oxythioquinox and the herbicide barban. One phenylcarbamate insect growth reatardant, H-24108, is weakly active in inhibiting Tribolium gut CS, as are three of its analogs but not 26 others. Many triazines are not inhibitory including several herbicides and an azido derivative, CGA 19255, which is active in blocking insect growth and chitin synthesis. Although the benzoylphenyl urea insecticides diflubenzuron and SIR 8514 are potent in vivo inhibitors of the polymerization step in insect chitin synthesis, they do not affect T. castaneum gut CS activity in vitro and greatly stimulate Tribolium brevicornis gut CS activity in vivo. These studies and preliminary findings on an integumental enzyme indicate that CS of these tissues is not sensitive to the direct action of benzoylphenyl ureas. This leads to speculation that the benzoylphenyl ureas act either as CS inhibitors via active metabolites formed in the integument or as blocking agents by direct binding to non-CS sites important in chitin polymerization and fibrillogenesis.     

Thiophene carboxamide fungicides: Structure-activity relationships with the succinate dehydrogenase complex from wild-type and carboxin-resistant mutant strains of Ustilago maydis

A variety of thiophene carboxamide compounds have been synthesized and tested on the succinate dehydrogenase complex (SDC) in mitochondria from a wild-type strain and carboxin-resistant strains of Ustilago maydis (corn smut). The site of action of thiophene carboxamides is identical to that of carboxin (5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxanilide) and thenoyltrifluoroacetone, that is, the succinate-ubiquinone reductase (complex II) span in the mitochondrial electron transfer chain. This investigation reveals new molecular structures which are strong inhibitors of wild-type and carboxin-resistant SDCs. The 5-amino analog of the parent anilide, 3-methylthiophene-2-carboxanilide (I), proved to be an especially potent inhibitor of the wild-type SDC (I₅₀, 0.019 μM). Analogs of (I) such as 4′-carboethoxy, 4′-nbutyl, 4′-phenyl, and 4′-benzoyl were negatively correlated in activity to the carboxanilide (I) with respect to resistance level. A number of structures showed considerable selectivity for mutated SDCs from both highly and (particularly) moderately carboxin-resistant SDCs of U. maydis, markedly lowering the resistance level, i.e., the degree of resistance. Thus, in addition to the oxathiins, specific structural groups of thiophene carboxamides can also alleviate or reverse the effect of carboxin-selected mutation with reference to inhibition of the SDC. Of important significance was the finding that molecular selectivity for mutated, carboxin-resistant SDCs can be influenced by replacement of an oxathiin by a thiophene heterocyclic ring as well as by the substitutive group on the amide nitrogen, permitting different categories of mutant types and even mutants within a single category to be distinguished from one another. With all the structural combinations available, it appears quite possible, in terms of inhibition, to overcome any type of mutation in a fungal SDC which arises through selection by carboxin or other carboxamide compounds. A reasonable correlation generally exists between inhibition by thiophene carboxamides of the SDC and sporidial growth of wild-type and carboxin-resistant strains of U. maydis. A permeability barrier to 4′-substituted analogs of (I) was encountered in the wild-type strain but not mutant strains. Excellent protectant activity against bean rust (Uromyces phaseoli) was obtained with the 3′-nhexyl, 3′-nhexyloxy, and 4′-phenoxy analogs of (I).     

Metabolism of N-hydroxymethyl dimethoate and N-desmethyl dimethoate in bean plants

N-Hydroxymethyl [carbonyl-¹⁴C] dimethoate (0.43 ppm) and N-desmethyl [carbonyl-¹⁴C] dimethoate (0.50 ppm) were stem-injected into bean plants (Phaseolus vulgaris) in two separate experiments. Plants were harvested periodically, extracted, fractionated, and analyzed for metabolites. The resulting pattern of metabolites formed from the administration of these two compounds was different. Radioactivity was not detected in the organic fraction 2 days after N-desmethyl dimethoate administration. N-Desmethyl dimethoate was rapidly broken down to dimethoate carboxylic acid and other polar metabolites, then further degraded into materials which became part of the plant constituents. N-Hydroxymethyl dimethoate was quite stable in the plant. Most of the material not remaining as parent became rapidly conjugated and constant levels of conjugate were maintained. Very little radioactivity was bound in the plant marc. The metabolic pathway of these compounds is as follows: N-hydroxymethyl to the glucoside or N-desmethyl derivative; the N-desmethyl metabolite degrades primarily to the carboxylic acid but also to N-desmethyl dimethoxon, either of which in turn may be degraded to dimethoxon carboxylic acid. The conversion of -NHCH₂OH to -NH₂ is a slow reaction so that conjugation becomes the route of choice when the plant is treated with N-hydroxymethyl dimethoate.     

Growth regulator inhibition of tobacco callus growth

The activity of two groups of growth regulators, substituted dinitroanilines and nitrophenylhydrazines, were evaluated in a tobacco (Nicotiana tabacum L. “X-73”) callus tissue bioassay. Molar concentrations required to inhibit fresh weight gain by 50% (I₅₀) was determined by using linear regression analysis on data obtained by testing a range of five concentrations of each chemical. All chemicals tested were inhibitory to callus tissue grown in the dark. Cell division seemed to be the primary activity inhibited. The most active of the dinitroaniline series was α,α,α-trifluoro-2,6-dinitro-N-ethyl-N-2′,6′-dichlorobenzyl-p-toluidine (I) (I₅₀ = 1.5 × 10^?10M). I and two other N-(o-halobenzyl) dinitroanilines were more active than α,α,α-trifluoro-2,6-dinitro-N-ethyl-N-2′-chloro-6′-fluorobenzyl-p-toluidine (IV), which is being developed commercially for suppression of axillary buds in tobacco. The two most active nitrophenylhydrazines tested were 1,1-dimethyl-2-(2′,6′-dinitro-3′-n-propylamino-α,α,α-trifluoro-p-tolyl)hydrazine (XVIII) and 3′,5′-dinitro-p-(2,2-diethylhydrazino)-N-methoxy-N-methylbenzamide (XIX) (I₅₀ values of 7.9 × 10^?9 and 9.3 × 10^?9M, respectively). Factors such as electronic distribution, steric hindrance, and lipid solubility were considered to influence the biological activity of the compounds tested.     

Jack bean urease inhibition by substituted ureas

The increased use of urea fertilizer and substituted ureas herbicides, the implication of soil urease in the effectiveness of urea applied as fertilizer, makes necessary to investigate their relationship.All herbicides investigated, fenuron, monuron, diuron, linuron, siduron and neburon are urease inhibitors. The inhibition constant value depends on molecular groups on the urea skeleton. There is a linear relationship between the Hammett sigma values and log Ki for fenuron, monuron and diuron.The presence of a large hydrophobic group and of one or two chlorine—an electron withdrawing group—on the phenyl ring of the herbicides molecule influences the Ki value.The hypothesis is proposed that the enzyme molecule reacts with inhibitors by means of the oxygen atom of the carboxyl group in the substituted ureas.     

Conversion of [14C]buturon in soil and leaching water under outdoor conditions

[¹⁴C]Buturon, a urea herbicide, was sprayed on soil and winter wheat as an aqueous formulation (2.98 kg/ha) under outdoor conditions. Three months after application, a total of 49.2% of the applied radiocarbon was recovered: 46.9% in the soil, 0.3% in the leaching water (depth > 50 cm), and 2.0% in the plants. Radioactive residues in the soil were distributed to a depth of 50 cm and decreased with increasing depth of the soil. An average of 47% of the radioactivity present in the soil could be extracted with cold chloroform; by this extraction method, the formation of artefacts was avoided. Between one and two thirds of the extracted radioactivity was unchanged buturon. In the soil extracts, the following eight conversion products were isolated and identified by combined gas chromatography/mass spectrometry: N-(p-chlorophenyl)-N-methyl-O-methyl carbamate; N-(p-chlorophenyl)-O-methyl carbamate; N-(p-chlorophenyl)-N′-methyl-N′-isobutenyl-urea; N-(p-chlorophenyl)-N′-methyl-urea, N-(p-chlorophenyl)-N′-methyl-N′-isobutenylol-urea; p-chloroaniline in “biologically bound” form; N-(p-chlorophenyl)-N′-methyl-N′-methoxyisobutenyl-urea; and N-(p-chlorophenyl)-N′-methyl-N′-ethoxyisobutenyl-urea. In the leaching water, which contained only 0.005–0.006 mg/liter of radioactive substances, the following three conversion products were isolated and identified by gas chromatography/mass spectrometry: p-chloroformanilide; N-(p-chlorophenyl)-N-methyl-O-methyl carbamate; and an N-hydroxyphenyl-N′-methyl-N′-isobutinyl-urea. The results are discussed in relation to the factors responsible for the formation of these products.     

Antifungal mode of action of triforine

Rapidly growing mycelia of Aspergillus fumigatus treated with 10 μg/ml triforine (N,N′-bis-(1-formamido-2,2,2-trichloroethyl)-piperazine) showed little or no inhibition in dry weight increase prior to 2 h. By 2.5–3 h, triforine inhibited dry weight increase by 85%. The effects of triforine on protein, DNA, and RNA syntheses corresponded to the effect on dry weight increase both in time of onset and magnitude. Neither glucose nor acetate oxidation were inhibited by triforine.Ergosterol synthesis was almost completely inhibited by triforine even in the first hour after treatment. Inhibition of ergosterol synthesis was accompanied by an accumulation of the ergosterol precursors 24-methylenedihydrolanosterol, obtusifoliol, and 14α-methyl-Δ^{8, 24 (28)}-ergostadienol. Mycelia treated with 5 μg/ml of triarimol (α-(2,4-dichlorophenyl)-α-phenyl-5-pyrimidinemethanol) also accumulated the same sterols as well as a fourth sterol believed to be Δ^{5, 7}-ergostadienol.Identification of 4,4-dimethyl-Δ^{8, 24 (28)}-ergostadienol in untreated mycelia indicates that the C-14 methyl group is the first methyl group removed in the biosynthesis of ergosterol by A. fumigatus. The lack of detectable quantities of 4,4-dimethyl-Δ^{8, 24 (28)}-ergostadienol in triforine or triarimol-treated mycelia and the accumulation of C-14 methylated sterols in treated mycelia suggests that both fungicides inhibit sterol C-14 demethylation. The accumulation of Δ^{5, 7}-ergostadienol in triarimol-treated mycelia further implies that triarimol also inhibits the introduction of the sterol C-22(23) double bond.Two strains of Cladosporium cucumerinum tolerant to triforine and triarimol were also tolerant to the fungicide S-1358 (N-3-pyridyl-S-n-butyl-S′-p-t-butylbenzyl imidodithiocarbonate).     

Diphenylether-like physiological and biochemical actions of S-23142, a novel N-phenyl imide herbicide

Several physiological and biochemical actions of a new experimental herbicide, S-23142 [N-(4-chloro-2-fluoro-5-propargyloxyphenyl)-3,4,5,6-tetrahydrophthalimide], have been investigated. S-23142 was active under the presence of light and oxygen. Photosynthetic CO₂ fixation in soybean began to decrease 4–5 hr after the foliar treatment of S-23142, being accompanied by the appearance of visible bleaching and wilting of the plants. A large amount of ethane, the products of peroxidation of unsaturated fatty acids, was produced from the cotyledon discs of cucumber (Cucumis sativus L.) treated with S-23142. Leakage of ATP was also observed. S-23142 did not inhibit photosynthetic oxygen evolution of the discs just after the application; however, the oxygen evolution rate decreased as the treated discs produced ethane. The results suggest that cell membrane and chloroplast membrane were deteriorated by the membrane lipid peroxidation. S-23142 also induced ethylene production and a high level of phenylalanine-ammonia lyase activity in cucumber cotyledon, which was regarded as the phenomena of stress response. Only the ethylene production was inhibited by aminoethoxyvinylglycine and cycloheximide, while the ethane production was not affected. All of these actions of S-23142 were essentially the same as those of acifluorfen ethyl except that the activity of S-23142 was more than 10 times higher than that of acifluorfen ethyl. These data strongly suggest that S-23142 belongs to the same group as diphenylethers in its mechanisms of action despite the difference in chemical structure.     

Enhanced excretion of DDT and metabolites in rats treated with trans,trans-muconate

The interactions between trans,trans-muconate and p,p′-DDT were examined. Male Wistar rats were injected intraperitoneally with 6.67 mg kg^?1 [¹⁴C]p,p′-DDT. Two hours later the experimental animals received orally a solution of sodium muconate (75 mg kg^?1, 0.3 ml) in physiological saline, pH 7.2; control animals received an equal volume of physiological saline. Treatment was repeated every 12 hr for 10 days. Sodium muconate does not modify urinary excretion of labeled compounds, yet it reduces body burden by accelerating the excretion rate of these compounds in rat feces. This action was observed only during the first 24 hr after the animals were exposed to p,p′-DDT.     

Inhibition of carotenogenesis by substituted diphenyl ethers of the m-phenoxybenzamide type

Diphenyl ethers exhibit different modes of action according to their chemical constitution. Diphenyl ethers of the m-phenoxybenzamide type, which were found to be effective on carotenogenesis resulting in an accumulation of colorless carotenoid precursors, mostly phytoene, indicative of inhibition of desaturation, are discussed. As seen with other carotenoid biosynthesis inhibitors, a concurrent loss of chlorophyll was observed as a secondary effect caused by the absence of protective carotenoids. In contrast to peroxidative p-nitrodiphenyl ethers like oxyfluorfen (2-chloro-4-trifluoromethylphenyl-3′-ethoxy-4′-nitrophenyl ether), the m-phenoxybenzamides assayed showed the same phytotoxic mode of action in the dark as observed when using heterotrophic Scenedesmus cultures. As expected, chlorophylls were not affected. The decrease of carotenoids was not due to their degradation but to inhibited carotenogenesis. Examination of carotenoid fractions show that the m-phenoxybenzamides, e.g., 3-(2,5-dimethylphenoxy)-N-ethylbenzamide, used here act similarly to 2-phenylpyridazinones like norflurazon [4-chloro-5-methylamino-2-(2-trifluoromethylphenyl)-pyridazin-3(2H)one]. All these inhibitors strongly decrease the α- and β-carotene content, while xanthophyll content is not lowered as much.     

Inhibition of DNA synthesis in boll weevils (Anthonomus grandis boheman) sterilized by dimilin

When boll weevils, Anthonomus grandis Boheman, were treated with dimilin (N-(4-chlorophenyl)-N′-(2,6-difluorobenzoyl)urea), the biosynthesis of deoxyribonucleic acid was inhibited in the female, but neither ribonucleic acid nor protein synthesis was affected. Treated males showed a difference in effect in lipoprotein synthesis, whereas no significant difference was demonstrated with females. Testicular growth was inhibited in some of the males. Diminishment of sexual function may therefore result in part from inhibition of biosynthesis of DNA by dimilin.