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N-Dephenylation of N-phenyl-2-naphthylamine (PBNA) is strictly limited in dogs, and a 5 mg/kg dose gives 0-10 microng of urinary 2-naphthylamine (BNA), which does not appear to undergo further metabolism. Neither 2-naphthylhydroxylamine (BNHA) nor 2-amino-1-naphthylsulphate were detected in the urine of treated animals. Urinary output of BNA varies markedly between dogs, and at different times in the same animal. The extent of PBNA N-dephenylation is unaltered by chronic administration. Calculations based on Druckery and Küpfmüller's equation (1948) and present data indicate that, for dogs to form BNA tumours through exposure to a relatively high dose-level of PBNA, the period of daily dosing would occupy, or even exceed, the normal life-span. The carcinogenic risk of PBNA to human subjects is discussed.

1. A single oral dose of [(14)C]Ionox 100 to rats is almost entirely eliminated in 11 days: 89.1-107.2% of the (14)C is excreted and 0.29+/-0.02% of the dose is present in the carcass plus viscera after removal of the gut. Rats exhibit an individual variation in the elimination pattern, 15.6-70.8% of (14)C being excreted in the urine and 75.2-27.0% in the faeces during 11 days. 2. After the oral administration of [(14)C]Ionox 100 to dogs, 87.1-90.3% of the (14)C is excreted in the faeces and urine during 4 days. 3. Dogs and rats do not show a species difference in this pattern of elimination. 4. The rate of elimination from dogs and rats given a single dose of Ionox 100 is not affected by the size of the dose and the presence of triglyceride fat in the diet. 5. Ionox 100 is completely metabolized in dogs and rats: unchanged Ionox 100 is absent from the urine and faeces, and from the carcass when elimination is complete. In rats, 3,5-di-tert.-butyl-4-hydroxybenzoic acid accounts for 50-85% of a dose of Ionox 100 and (3,5-di-tert.-butyl-4-hydroxybenzoyl beta-d-glucopyranosid)uronic acid for 47-10%; in dogs, the unconjugated acid accounts for 85% and the ester glucuronide for 10-12%. 3,5-Di-tert.-butyl-4-hydroxyhippuric acid is not formed. Other metabolites, which have been detected in small quantity in the faeces and urine of animals dosed with Ionox 100, have not been identified. 6. 3,5-Di-tert.-butyl-4-hydroxybenzoic acid and (3,5-di-tert.-butyl-4-hydroxybenzoyl beta-d-glucopyranosid)uronic acid are also the major metabolites of Ionol (2,6-di-tert.-butyl-p-cresol) in rats. 7. The elimination of Ionox 100 metabolites from rats is faster than that of Ionol and its metabolites. Unlike Ionol, unchanged Ionox 100 could not be detected in the bodies of these animals.

1. Up to one-third of a single oral dose of Ionox 201 was absorbed in rats. 2. In rats dosed with [(14)C]Ionox 201 86.8-97.2% of the label is excreted in the faeces in 24 days (much of this is eliminated in the first 4 days after dosage), 5.6% in the urine and not more than 0.8% in the exhaled air; 5.0% of (14)C is present in the carcass and viscera after removal of the gut, and most of this is in the fatty tissues. 3. About 65.0% of (14)C in the faeces is due to unchanged antioxidant, 30.0% to 3,5-di-tert.-butyl-4-hydroxybenzoic acid, 3.5% to unidentified polar constituent(s), 1.4% to 3,5-di-tert.-butyl-4-hydroxybenzaldehyde and 0.1% to 3,3',5,5'-tetra-tert.-butyl-4-,4'-stilbenequinone. A variable proportion of (14)C in the urine is due to 3,5-di-tert.-butyl-4-hydroxybenzoic acid (40-60%) and the remainder (60-40%) to the ester glucuronide, when the animals were treated with different doses of antioxidant. In eight individual animals dosed with 6.78mg. of [(14)C]Ionox 201, one-third of (14)C in the bile is due to the free acid, 45% to the ester glucuronide, 20% to an unidentified constituent and 2% to unchanged antioxidant, and, in two animals dosed with 13.56mg., there is a small proportion of free acid and a larger proportion of ester glucuronide. About 80% of (14)C in the body fat is due to unchanged antioxidant, 19% to the free acid and 1% to 3,5-di-tert.-butyl-4-hydroxybenzaldehyde. 4. At least 36.2% of a single oral dose of Ionox 201 is metabolized: 3,5-di-tert.-butyl-4-hydroxybenzoic acid accounts for 30.2% of a dose, (3,5-di-tert.-butyl-4-hydroxybenzoyl beta-d-glucopyranosid)uronic acid for 1.4%, 3,5-di-tert.-butyl-4-hydroxybenzaldehyde for 1.3%, 3,3',5,5'-tetra-tert.-butyl-4,4'-stilbenequinone for 0.1% and unidentified polar metabolite(s) for 3.2%. 5. The metabolism of Ionox 201 in vivo is closely related to its antioxidant action in vitro.

1. A large proportion of a single oral dose of [14C]Ionox 220 to rats is eliminated in 24 days: 89·3–97·4% of the label is excreted in the faeces (much of this is eliminated in the first 4 days after dosage), 1% in the urine and less than 0·1% in the expired gases; 4·06% of 14C is present in the carcass and viscera after removal of the gut, and most of this is in the fatty tissues. 2. About 87% of 14C in the faeces is due to unchanged antioxidant, 5% to the quinone methide, 5% to the free acid and 3% to an unidentified polar constituent. Three-fifths of 14C in the urine is due to 3,5-di-tert.-butyl-4-hydroxybenzoic acid and the remainder to the ester glucuronide. In three individual animals, one-half of 14C in the bile is due to the free acid, one-quarter to the ester glucuronide and the remainder to unchanged antioxidant, whereas in another all of 14C in the bile is due to Ionox 220. About 97% of 14C in the body fat is due to unchanged antioxidant and the remainder to the free acid. 3. Up to 20% of a single oral dose of Ionox 220 is absorbed in rats: 13–14% is metabolized. 3,5-Di-tert.-butyl-4-hydroxybenzoic acid accounts for just over 5% of a dose of Ionox 220, 3,5-di-tert.-butyl-4-hydroxybenzoyl-β-d-glucopyranosiduronic acid for less than 0·4%, the quinone methide for just over 5% and an unidentified compound for less than 3%. 4. The physiological and biochemical implications of ingesting Ionox 220 are discussed.

1. A number of synthetic indole compounds have been tested as antagonists for 5-hydroxytryptamine (HT) in experiments on rat's uterus. 2. Antagonisms are classified as unspecific except when it has been possible to inhibit the response to HT without altering the response to acetylcholine. 3. The time course of the antagonisms has been followed by estimating the dose-ratio: that is, the ratio of equiactive doses of HT before and after the administration of the antagonist. 4. The activity of different compounds has been compared by estimating the drug-ratio, which is equal to the ratio of the dose of HT to the dose of antagonist, when the effect after 1 hour is 50 per cent of the original maximal effect. This gives results in general agreement with estimates of the pA2, and is more convenient when there are many substances to be tested. 5. The effects of the more active compounds, such as dibenamine, lysergic acid diethylamide and benzyloxygramine, developed slowly and became irreversible. Eventually the blockade could not be overcome even by enormous doses of HT, and it is then said to be unsurmountable. 6. The effects of less active specific antagonists (such as methylgramines) developed more rapidly, and were reversible and surmountable.

14C02 output from carboxy-14C-labelled aliphatic carboxylic acids is measured in the micro-scale Kolbe reaction. Irrespective of whether rats were dosed with 1,1-dichloro[1-14C]ethylene or with chloro[1-14C]acetic acid, 1 mol.equiv. of the resulting thio[14C]diglycollic acid yields by electrolysis approx. 0.7 equiv. of 14CO2, which is interpreted in terms of the labelling of one of the carboxylic acid groups of thiodiglycollic acid. This observation provides important evidence concerning thiodiglycollic acid biosynthesis from 1.1-dichloroethylene.

Up to 88% of a single dose of methyl[14C]methacrylate in rats is expired as 14CO2 in 10 days (65% in 2 h), irrespective of the route of administration and of the specific labelling of the propylene residue of the molecule. The implications of this observation, and of the excretion of small amounts of [14C]methylmalonate, [14C]-succinate and probably of [14C]beta-hydroxyisobutyrate and 2-formylpropionate, and of the formation of [14C] normal, physiological metabolites that may be accounted for by anabolism both from 14CO2 and from [14C]acetate emergent from the citric acid cycle, are that the metabolic pathway concerned involves intermediary metabolism and relates to mitochondrial function. Present findings are discussed in relation to the imputations of a report of carcinogenic risk.

1. Unchanged Ionox 330 is quantitatively eliminated in the faeces of dogs, rats and man after oral administration, and (14)C is absent from the urine and expired gases of rats intubated with [(14)C]Ionox 330. Dogs and rats do not show a sex difference in this pattern of elimination. 2. Quantitative elimination of [(14)C]Ionox 330 and the absence of (14)C in the carcass and viscera of rats 72hr. after dosage show that this substance does not accumulate in the body. 3. No metabolites are formed in consequence of the ingestion of Ionox 330. 4. Rats eliminate three-quarters or more of a dose (285.7mg./kg. body wt.) of Ionox 330 in 24hr. and the remainder during 24-48hr., and dogs eliminate the whole dose (90mg./kg. body wt.) within 48hr. and a variable proportion within 24hr. These rates of elimination are consistent with the passage of unabsorbed material through the alimentary canal. 5. After removal of the alimentary canal, radioactivity is absent from the carcass and remaining viscera of rats 8, 16 and 24hr. after ingestion of [(14)C]Ionox 330, and this strongly suggests the absence of alimentary absorption. 6. The absence of (14)C in the 24hr. bile of animals with biliary fistulae establishes that [(14)C]Ionox 330 is not absorbed from the gastro-intestinal tract.

1. A single oral dose of [(14)C]Chlorfenvinphos to rats is quantitatively eliminated in 4 days. Rats do not show a sex difference in the elimination pattern and show only a small degree of biological variation in the total excretion data. Of the label 87.2% is excreted in the urine (67.5% in the first day after dosage), 11.2% in the faeces and 1.4% in the expired gases; less than 0.9% of (14)C is present in the gut and contents after 4 days. 2. After oral administration of [(14)C]Chlorfenvinphos to dogs, 94.0% (91.8-97.6%) of the (14)C is excreted in the urine and faeces during 4 days. Dogs do not show a sex difference in the pattern of elimination, and excretion of radioactivity in the urine is very rapid: 86.0% of (14)C during 0-24hr. 3. Chlorfenvinphos is completely metabolized in rats and dogs: unchanged Chlorfenvinphos is absent from the urine and from the carcass, when elimination is complete. In rats, 2-chloro-1-(2',4'-dichlorophenyl)vinyl ethyl hydrogen phosphate accounts for 32.3% of a dose of Chlorfenvinphos, [1-(2',4'-dichlorophenyl)ethyl beta-d-glucopyranosid]uronic acid for 41.0%, 2,4-dichloromandelic acid for 7.0%, 2,4-dichlorophenylethanediol glucuronide for 2.6% and 2,4-dichlorohippuric acid for 4.3%; in dogs, 2-chloro-1-(2',4'-dichlorophenyl)vinyl ethyl hydrogen phosphate accounts for 69.6%, [1-(2',4'-dichlorophenyl)ethyl beta-d-glucopyranosid] uronic acid for 3.6%, 2,4-dichloromandelic acid for 13.4% and 2,4-dichlorophenylethanediol glucuronide for 2.7%. 4. Dogs and rats show a species difference in the rate of excretion of (14)C in the urine, and in the proportions of the metabolites, with the exception of 2,4-dichlorophenylethanediol glucuronide, that are excreted in the urine. Alternative explanations for the latter species difference are suggested. 5. 2-Chloro-1-(2',4'-dichlorophenyl)vinyl ethyl hydrogen phosphate and 2,4-dichlorophenacyl chloride probably lie on the main metabolic pathway of Chlorfenvinphos, since, in common with that insecticide, they give rise to [1-(2',4'-dichlorophenyl)ethyl beta-d-glucopyranosid]uronic acid and 2,4-dichloromandelic acid as major metabolites in the urine. 6. The proposed scheme for the metabolism of Chlorfenvinphos represents a detoxication mechanism.

1. Increases in the concentrations of lactic acid and pyruvic acid in rat brain during acute dieldrin poisoning are associated with hyperactivity of the brain, whereas an increase in the cerebral alanine concentration occurs before the convulsions. Throughout the dieldrin-induced seizure pattern, fluctuations in the concentration of brain ammonia are out of phase with the actual convulsions. 2. Increases in the concentrations of alanine, ammonia and lactic acid in rat brain accompany picrotoxin-induced seizures; there is no increase in the concentration of glutamine. These changes are consistent with the inhibition of glutamine synthesis. 3. In addition to previously reported changes in the concentrations of intermediary metabolites of the brain after the administration of Telodrin (Hathway & Mallinson, 1964), increases have now been found in the alanine and lactic acid concentrations. Since increases in the alanine and glutamine concentrations occur before the convulsions, liberation of ammonia also occurs before the onset of convulsions and throughout their course. Ammonia-binding mechanisms later become inadequate and free ammonia accumulates in cerebral tissues. 4. An increase in the pyruvic acid concentration of the brain after the intraperitoneal injection of either dieldrin or Telodrin is endogenous in origin. 5. The parenteral administration of a small dose of glutamine increases the cerebral concentrations of alanine and glutamic acid. Some animals previously treated with glutamine resisted Telodrin convulsions. 6. Mechanisms for the disposal of ammonia liberated in brain are discussed.

CHROMATOGRAPHIC and spectrophotometric properties of ellagic acid have now been investigated in order to facilitate the identification of this acid in plant extracts and hydrolysates. In early studies, ellagic acid has not always been adequately characterized; but the present work has confirmed the occurrence of this substance in a wide range of dicotyledonous plants1. Ellagic acid has also been identified in Terminalia arjuna, bellirica, citrina, pallida and travencoriensis for the first time.

An exploratory study of those reactions of catechin which lead to polymer formation has enabled the conditions for autoxidation to be defined. The formation of polymers and hydrogen peroxide during the autoxidation at 35 and pH6-8 of catechin and of related 3': 4'-dihydroxyflavans has been studied by measurement of oxygen uptake, and by absorption spectra, colour reactions and chromatographic properties of the polymers, and by elementary analyses of the electrodialysed polymers (1). The evidence obtained together with that provided by spectroscopic study of intermediates produced by silver oxide oxidation (2) support the theory of quinone polymerisation for the autoxidation of catechin. Whereas quinone polymerisation of catechin and 5:7:3':4'-tetrahydroxyflavan involves the phloroglucinol residue, oxidative coupling of 5:7-di-0-methylcatechin and 3':4'-dihydroxyflavan resembles that of catechol. Further evidence for head-to-tail quinone polymerisation of catechin has been found in studies of the autoxidation of mixed phenolic substrates. Enzymic oxidation by mushroom, potato and tobacco polyphenoloxidases proceeds at a faster rate and lower temperature than the autoxidation of catechin, and gives a product precisely similar to the autoxidation polymer. The rate of oxygen uptake is proportional to the enzyme concentration The significance of the autoxidation and enzymic oxidation of catechin to the formation of phlobatannins is considered. Oxidation polymers of catechin are comparable with the tannins which have now been isolated in relatively large amounts from amongst tannin extracts of Acacia catechu and Uncaria gambir, plants valued for their phlobatannins (3). Special sections summarise the chemistry of catechin, the physical techniques on which much of this work depends, and the application of the theory of condensation polymerisation to the polymerisation of catechin. Three flavonols have been identified in extracts from Acacia catechu.

The Chemistry of Tanning Processes By K. H. Gustavson. Pp. ix + 403. (New York: Academic Press, Inc.; London: Academic Books, Ltd., 1956.) 9 dollars.