- Email: [email protected]
2248. Getting rid of benzoic acid
PRESERVATIVES
907
The metabolism of the antioxidant 2,6-di-tert-butyl-4-hydroxymethylphenol (Ionox 100) has been reported previously (Cited in F.C.T. 1966, 4, 229). The present study reports acute, long-term and multigeneration feeding studies on this compound. The single dose LDso in rats and mice was found to be greater than 7 g/kg, the maximum dose that the animals' stomachs could accommodate. In the 2-yr feeding study, the antioxidant was incorporated at a level of 0.2 or 0.35~o into the diet of groups of 20 male and 20 female rats. There were no significant differences in survival, terminal organ weights, pathology, haematology or serum-enzyme levels between the treated and control animals, but the treated animals showed a greater increase in body weight than the controls. Finally no evidence of any adverse effects on fertility and mating was observed in a three-generation reproduction study using rats fed a diet containing 0-35~ Ionox 100 continuously from weaning. The test thus established a no-effect level of 0"35~o in the diet of rats, equivalent to an intake of 175 mg/kg/day, which can be taken to indicate an acceptable daily intake for man of 1.75 mg/kg. [The body-weight values given for the 2-yr study indicate that the increases in the treated rats were statistically significant (P < 0-001) throughout the experiment at the 0.35~ level in both sexes and at the 0.2~ level in the males. They were, however, associated with an increased food intake when compared with the controls, an effect which may perhaps have been due to the development of some rancidity and consequent unpalatability in the control diet while the diet of the treated animals was protected by the antioxidant.]
PRESERVATIVES 2248. Getting rid of benzoic acid Bridges, J. W., French, M. R., Smith, R. L. & Williams, R. T. (1970). The fate of benzoic acid in various species. Biochem. J. 118, 47. We referred some time ago (Cited in F.C.T. 1967, 5, 576) to the fact that benzoic acid (BA), used in foods as a preservative and in certain pharmaceutical preparations, is detoxicated by some mammalian species principally by conjugation with glycine to form hippuric acid (benzoylglycine; HA), although there is a marked species difference in the efficiency of this process. Further indication of the considerable differences that exist in the way animals dispose of BA has now been provided by a study of the urinary excretion of metabolites of BA, administered as sodium ['4C]benzoate, in man and 20 other species. After an oral dose of 50 mg BA/kg most species excreted 50-100~o of 14C activity in the urine in the first 24 hr. In the turtle and gecko, however, excretion was slower, reaching only 39~o in 3 days. In herbivorous and omnivorous species (rhesus, squirrel and capuchin monkeys and the pig, rabbit, rat, mouse, guinea-pig, hamster, lemming and gerbil) BA was excreted in the urine almost entirely as HA, though 10--20~ of the total 14C activity appeared as free BA in pigs and squirrel monkeys within 24 hr, possibly as a result of the decomposition of benzoyl glucuronide. In the two men given 1 mg BA/kg, almost all the urinary metabolite was HA, with 97~o of the ~4C activity excreted within 4 hr and virtually 100~o within 12 hr. In the carnivorous animals tested (dog, cat and ferret) the principal metabolite was again HA, with the dog and ferret excreting also some benzoyl glucuronide. A similar excretion occurred in the hedgehog, an insectivore. The Indian fruit bat (Pteroptus giganteus), on the other hand, excreted 70--80~o of BA as the glucuronide and the remainder as the
908
AGRICULTURAL CHEMICALS
free acid within 24 hr. The pigeon excreted mainly HA and not ornithuric acid, which was the major end-product in the chick, turtle and gecko. When the dose of BA in the ferret was raised to 200 and 400 mg/kg, the proportion excreted as the glucuronide was markedly increased. The observations indicate that BA is not destroyed in any of the species tested, but that the relative amount of conjugation with glycine and with glucuronic acid varies from species to species and may depend to some extent upon the magnitude of the dose.
2249. A safety margin for injected benzyl alcohol Kimura, E. T., Darby, T. D., Krause, R. A. & Brondyk, H. D. (1971). Parenteral toxicity studies with benzyl alcohol. Toxic. appl. Pharmac. 18, 60. The pharmacology of benzyl alcohol (I) was studied many years ago, and the compound has since been extensively used in pharmaceutical preparations, particularly in those intended for multidose injection, on account of its preservative action and mild local anaesthetic activity. The study here described arose from the observation that the rapid injection of 0-9% I in saline had killed mice. Many drug injections in multidose containers contain 0.9% I, and it is possible that a patient might inadvertently receive up to 30 ml of the injection fluid into a vein in one dose. Slow intravenous injection of 1 ml 0.9% I/kg into unanaesthetized and anaesthetized dogs and anaesthetized monkeys failed to alter the blood pressure, heart rate, respiration or ECG pattern, and produced no changes in the haematological picture. Intracarotid and intrarenal injection of the same dose into anaesthetized dogs did not affect either these parameters or the EEG tracing. The lethal intravenous dose of I in anaesthetized dogs was 830-1060 mg/kg, the LDso in rats was 314 mg/kg, and in mice 480 mg/kg was uniformly fatal when injected rapidly. In rats, 94% I was 23 times more toxic intravenously than 95% ethanol, and again in mice, in which the LDso of I was below 480 mg/kg, the LDso for 95% ethanol was 1460 mg/kg. A safety factor of about 38 was calculated for a 30-ml dose of 0.9% I injected into a 50-kg adult. A G R I C U L T U R A L CHEMICALS
2250. Working with 2,4,5-T Poland, A. P., Smith, D., Metter, G. & Possick, P. (1971). A health survey of workers in a 2,4-D and 2,4,5-T plant. With special attention to chloracne, porphyria cutanea tarda, and psychologic parameters. Archs envir. Hlth 22, 316. The recent and continuing arguments about the possible teratogenic effects of 2,4,5trichlorophenoxyacetic acid (2,4,5-T) have tended to overshadow other questions about possible hazards associated with its handling during manufacture or use. However, the paper cited above reports on the medical problems associated with production of this herbicide, following a survey of 73 male workers in a 2,4,5-T factory. Chloracne, characterized by inclusion cysts, comedones and pustules, was found in 13 workers, and was correlated in severity with the presence of scarring, hyperpigmentation, hirsutism and complaints of eye irritation. There was also a significant correlation with hypomania, in contrast to the lethargy, dulled emotional response and apathy described previously in
907
The metabolism of the antioxidant 2,6-di-tert-butyl-4-hydroxymethylphenol (Ionox 100) has been reported previously (Cited in F.C.T. 1966, 4, 229). The present study reports acute, long-term and multigeneration feeding studies on this compound. The single dose LDso in rats and mice was found to be greater than 7 g/kg, the maximum dose that the animals' stomachs could accommodate. In the 2-yr feeding study, the antioxidant was incorporated at a level of 0.2 or 0.35~o into the diet of groups of 20 male and 20 female rats. There were no significant differences in survival, terminal organ weights, pathology, haematology or serum-enzyme levels between the treated and control animals, but the treated animals showed a greater increase in body weight than the controls. Finally no evidence of any adverse effects on fertility and mating was observed in a three-generation reproduction study using rats fed a diet containing 0-35~ Ionox 100 continuously from weaning. The test thus established a no-effect level of 0"35~o in the diet of rats, equivalent to an intake of 175 mg/kg/day, which can be taken to indicate an acceptable daily intake for man of 1.75 mg/kg. [The body-weight values given for the 2-yr study indicate that the increases in the treated rats were statistically significant (P < 0-001) throughout the experiment at the 0.35~ level in both sexes and at the 0.2~ level in the males. They were, however, associated with an increased food intake when compared with the controls, an effect which may perhaps have been due to the development of some rancidity and consequent unpalatability in the control diet while the diet of the treated animals was protected by the antioxidant.]
PRESERVATIVES 2248. Getting rid of benzoic acid Bridges, J. W., French, M. R., Smith, R. L. & Williams, R. T. (1970). The fate of benzoic acid in various species. Biochem. J. 118, 47. We referred some time ago (Cited in F.C.T. 1967, 5, 576) to the fact that benzoic acid (BA), used in foods as a preservative and in certain pharmaceutical preparations, is detoxicated by some mammalian species principally by conjugation with glycine to form hippuric acid (benzoylglycine; HA), although there is a marked species difference in the efficiency of this process. Further indication of the considerable differences that exist in the way animals dispose of BA has now been provided by a study of the urinary excretion of metabolites of BA, administered as sodium ['4C]benzoate, in man and 20 other species. After an oral dose of 50 mg BA/kg most species excreted 50-100~o of 14C activity in the urine in the first 24 hr. In the turtle and gecko, however, excretion was slower, reaching only 39~o in 3 days. In herbivorous and omnivorous species (rhesus, squirrel and capuchin monkeys and the pig, rabbit, rat, mouse, guinea-pig, hamster, lemming and gerbil) BA was excreted in the urine almost entirely as HA, though 10--20~ of the total 14C activity appeared as free BA in pigs and squirrel monkeys within 24 hr, possibly as a result of the decomposition of benzoyl glucuronide. In the two men given 1 mg BA/kg, almost all the urinary metabolite was HA, with 97~o of the ~4C activity excreted within 4 hr and virtually 100~o within 12 hr. In the carnivorous animals tested (dog, cat and ferret) the principal metabolite was again HA, with the dog and ferret excreting also some benzoyl glucuronide. A similar excretion occurred in the hedgehog, an insectivore. The Indian fruit bat (Pteroptus giganteus), on the other hand, excreted 70--80~o of BA as the glucuronide and the remainder as the
908
AGRICULTURAL CHEMICALS
free acid within 24 hr. The pigeon excreted mainly HA and not ornithuric acid, which was the major end-product in the chick, turtle and gecko. When the dose of BA in the ferret was raised to 200 and 400 mg/kg, the proportion excreted as the glucuronide was markedly increased. The observations indicate that BA is not destroyed in any of the species tested, but that the relative amount of conjugation with glycine and with glucuronic acid varies from species to species and may depend to some extent upon the magnitude of the dose.
2249. A safety margin for injected benzyl alcohol Kimura, E. T., Darby, T. D., Krause, R. A. & Brondyk, H. D. (1971). Parenteral toxicity studies with benzyl alcohol. Toxic. appl. Pharmac. 18, 60. The pharmacology of benzyl alcohol (I) was studied many years ago, and the compound has since been extensively used in pharmaceutical preparations, particularly in those intended for multidose injection, on account of its preservative action and mild local anaesthetic activity. The study here described arose from the observation that the rapid injection of 0-9% I in saline had killed mice. Many drug injections in multidose containers contain 0.9% I, and it is possible that a patient might inadvertently receive up to 30 ml of the injection fluid into a vein in one dose. Slow intravenous injection of 1 ml 0.9% I/kg into unanaesthetized and anaesthetized dogs and anaesthetized monkeys failed to alter the blood pressure, heart rate, respiration or ECG pattern, and produced no changes in the haematological picture. Intracarotid and intrarenal injection of the same dose into anaesthetized dogs did not affect either these parameters or the EEG tracing. The lethal intravenous dose of I in anaesthetized dogs was 830-1060 mg/kg, the LDso in rats was 314 mg/kg, and in mice 480 mg/kg was uniformly fatal when injected rapidly. In rats, 94% I was 23 times more toxic intravenously than 95% ethanol, and again in mice, in which the LDso of I was below 480 mg/kg, the LDso for 95% ethanol was 1460 mg/kg. A safety factor of about 38 was calculated for a 30-ml dose of 0.9% I injected into a 50-kg adult. A G R I C U L T U R A L CHEMICALS
2250. Working with 2,4,5-T Poland, A. P., Smith, D., Metter, G. & Possick, P. (1971). A health survey of workers in a 2,4-D and 2,4,5-T plant. With special attention to chloracne, porphyria cutanea tarda, and psychologic parameters. Archs envir. Hlth 22, 316. The recent and continuing arguments about the possible teratogenic effects of 2,4,5trichlorophenoxyacetic acid (2,4,5-T) have tended to overshadow other questions about possible hazards associated with its handling during manufacture or use. However, the paper cited above reports on the medical problems associated with production of this herbicide, following a survey of 73 male workers in a 2,4,5-T factory. Chloracne, characterized by inclusion cysts, comedones and pustules, was found in 13 workers, and was correlated in severity with the presence of scarring, hyperpigmentation, hirsutism and complaints of eye irritation. There was also a significant correlation with hypomania, in contrast to the lethargy, dulled emotional response and apathy described previously in