Herman J. Benezet

Formamidine Pesticides — Metabolic Aspects of Neurotoxicity

Formamidines are a relatively new class of agricultural chemicals, and within this group there exist diverse types of pesticidal activity. For example, compounds active as herbicides, fungicides, nematocides, bactericides, insecticides, and acaricides have been discovered. The insecticide and acaricide N′-(4-chloro-o-tolyl)-N,N-dimethylformamidine or chlordimeform has received the most attention from a toxicological standpoint since it has been used extensively for insect and acarine control (Knowles, 1976).

Microbial degradation of thidiazuron and its photoproduct.

Degradation of the cotton defoliant thidiazuron and its photoproduct photothidiazuron by soil and thirteen species of microorganisms was examined.Aspergillus versicolor, Torula rosea, andFlavobacter sp. were most active in degrading thidiazuron. Unknown water-soluble metabolites and phenylurea were the major products.A. versicolor andPenicillium cyclopium were most active in degrading photothidiazuron. 4-Hydroxyphenylphotothidiazuron was the major organosoluble product formed byA. versicolor; phenylurea and an unidentified metabolite constituted the major organo-soluble products fromP. cyclopium. Both microbes also formed appreciable water-soluble metabolites. Radioactive carbon dioxide was formed from thidiazuron-aniline-14C byOscillatoria sp. but not byChlorella sp., suggesting that the former algal species utilized the defoliant as an energy source.

Further studies of the monoamine oxidase inhibiting activity of formanilides and formamidines

Abstract 1. 1. Five substituted formanilides and their corresponding N,N-dimethylformamidine derivatives were examined for their potency as in vitro inhibitors of rat brain mitochondrial monoamine oxidase (MAO) with serotonin and β-phenylethylamine as substrates. 2. 2. Formanilides were selective, competitive inhibitors of MAO-A (serotonin oxidation). 3. 3. The most potent formanilide MAO-A inhibitor was 2,4,5-trichloroformanilide with an I50 value of 0.045 μM. 4. 4. The most selective formanilide MAO-A inhibitor was 5-chloro-2,4-dimethoxyformanilide with I50 values of 0.95 μM for MAO-A and > 10,000 μM for MAO-B (β-phenylethylamine oxidation). 5. 5. Formamidines were neither as potent nor as selective inhibitors in vitro as their corresponding formanilides. 6. 6. 5-Chloro-2,4-dimethoxyformanilide and N′-(5-chloro-2,4-dimethoxyphenyl)-N,N-dimethylformamidine also inhibited rat brain MAO in vivo following intraperitoneal injection; the formanilide was more potent and more selective.

Thidiazuron uptake, distribution and metabolism in bluegills and channel catfish 1

Bluegills (Lepomis macrochirus) exposed to 0.1 ppm of thidiazuron-14C cotton defoliant for 28 days under continuous flow conditions accumulated relatively low levels of radiocarbon. The maximum detected was 5.4 ppm in fillet tissue after 1 day. During a 14 day depuration period, radioactivity declined to 1.0 ppm or less. Fractionation of offal and fillet tissues from bluegills collected at 28 days indicated that most of the radioactive material was water soluble, although appreciable amounts of organosoluble radioactive material also were present. When bluegills were injected intraperitoneally with thidiazuron-14C, metabolism and elimination were relatively rapid. Organosoluble radioactive material isolated from fish tissue included thidiazuron, its 2-hydroxyphenyl derivative, phenylurea, and several unknowns. Channel catfish (Ictalurus punctatus) exposed under static conditions to a system containing 0.15 ppm of thidiazuron-14C incorporated into soil also accumulated only low concentrations of radiocarbon. The maximum detected was 2.5 ppb in offal tissue at 7 days. In fillet tissue, radioactivity did not exceed 0.5 ppb. There was no evidence from these studies to indicate that thidiazuron would pose a hazard to the aquatic ecosystem.

Inhibition of ethanol and acetate metabolism in mice by chlordimeform and related compounds

Abstract 1. Since chlordimeform or N ′-(4-chloro- o -toly l )- N , N -dimethylformamidine and certain of its mammalian metabolites prolong ethanol induced sleep in mice, their effect on ethanol and acetate metabolism was examined. 2. Intraperitoneal treatment of mice with chlordimeform (50 mg/kg) and demethylchlordimeform or N ′-(4-chloro- o -tolyl)- N -methylformamidine (50 mg/kg), the two most potent sleep inducers, appreciably inhibited the metabolism of ethanol to 14 CO 2 . Another metabolite, 4-chloro- to -formotoluidide (100 mg/kg), a very weak sleep inducer, also markedly inhibited ethanol metabolism. 3. Chlordimeform, demethylchlordimeform, and 4-chloro- o -formotoluidide inhibited the conversion of ethanol to 14 CO 2 and the conversion of acetate to 14 CO 2 in vitro by mouse liver preparations. 4. The potency of 4-chloro- o -formotoluidide as an inhibitor of acetate metabolism in vitro compared favorably with that of SKF-525A, a known inhibitor of microsomal mixed function oxidases. 5. At a concentration of 1 × 10 −3 M, demethylchlordimeform yielded 27.4% inhibition of yeast alcohol dehydrogenase as compared to 46.3% for thiourea, a known inhibitor of this enzyme. The other compounds gave little, if any, inhibition of yeast alcohol or aldehyde dehydrogenase. 6. Although it is not possible to explain the mechanism for ethanol sleep enhancement in mice by chlordimeform and its metabolite demethylchlordimeform, inhibition of the alcohol dehydrogenase by demethylchlordimeform may be significant in this connection. 7. The decrease in ethanol metabolism apparently was due in large part to the activity of chlordimeform, demethylchlordimeform and especially 4-chloro- o -formotoluidide as inhibitors of microsomal mixed function oxidases.